New tricyclic quinone derivative

ABSTRACT

This invention provides a compound represented by formula (1) or a pharmaceutically acceptable salt thereof. Specifically, the present invention provides a compound represented by formula (1) or a pharmaceutically acceptable salt thereof [Therein, A is O, S, or N—R 6 ; ring G is a 5-membered or 6-membered aromatic ring, etc., including 1-3 heteroatoms selected from O, S and N as constituent atoms; R 1  and R 2  are each independently a hydrogen atom, a halogen atom, or an optionally-substituted C 1-6  alkyl carbonyl group, etc.; R 3 , R 4  and R 5  are each independently a hydrogen atom, a halogen atom, or an optionally-substituted C 1-6  alkyl carbonyl group, etc.; and R 6  is a hydrogen atom or an optionally-substituted C 1-6  alkyl group, etc.].

TECHNICAL FIELD

The present invention relates to novel tricyclic quinone derivativesuseful as medicament or a pharmacologically acceptable salt thereof.More particularly, the invention relates to pharmaceutical compositionscomprising a novel tricyclic quinone derivative or a pharmacologicallyacceptable salt thereof. The invention relates to therapeutic agentscomprising a novel tricyclic quinone derivative comprising the compound,or a pharmacologically acceptable salt thereof.

BACKGROUND ART

Cancer develops when abnormality in gene occurs by an action ofradiation, ultra violet rays, carcinogen, virus, or the like. The numberof deaths by cancer increases year by year, and cancer is currently thetop cause of death in Japan. As means for such cancer therapy, antitumoragents, surgical operation, radiotherapy, immunotherapy, and the likeare performed. However, among these, the therapeutic use of an antitumoragent is the most important as an internally therapeutic means. Majorantitumor agents act on any of metabolism, DNA synthesis, RNA synthesis,or protein synthesis of a nucleic acid precursor. However, suchmetabolic processes occur in not only cancer cells, but also normalcells. Therefore, many antitumor agents act on not only on cancer cells,but also on normal cells, and consequently any types of side effectsdevelop.

In recent years, a new type of antitumor agent, called moleculartargeting agent, has been introduced. This molecular targeting agent isa pharmaceutical agent designed to target a molecule specificallyexpressed in each cancer. Therefore, it is believed that a moleculartargeting agent has higher specificity to cancer cells than conventionalantitumor agents, and has fewer side effects. However, with regard tomolecular targeting agents, although previous side effects are reduced,there are problems that new side effects are exhibited and alternativesof pharmaceutical agents are limited. Although the aforementionedantitumor agents were clinically used for the purpose of cancer therapyand prolonging the life of a cancer patients, there are still a numberof unsolved problems including problems of side effects and the like asdescribed above. Accordingly, it is recognized that the development of anovel antitumor agent is an important topic in the future.

In recent studies, the existence of cancer stem cells (CSC) havingreplication competence has been revealed, the CSC is closely related tothe malignant transformation of cancer. In nearly all of major types ofcancer in human, such as breast cancer, colon cancer, lung cancer,hematological malignancy, and the like, CSCs are identified. A CSC and anormal cancer cell differentiated from the CSC are significantlydifferent in biological characteristics. A CSC is shown to be importantin continuous proliferation of malignant tumor, metastasis andrecurrence of cancer, and its resistance to an antitumor agent. AlthoughConventional therapy that targets normal cancer cells accounting formost part of tumor lumps can reduce the size of a tumor, as long as aCSC is also targeted at the same time, a meaningful survival effectcannot be expected. Therefore, targeting a CSC is very promising as anew method to treat a cancer (Non Patent Literature 1). One of thecharacteristics of CSCs is to have replication competence. Reliablemethods established as a method of measuring replication competence of acell include measurement of cancer cell sphere-forming ability innon-adhesion state in the absence of serum (Non Patent Literature 2). Acompound that inhibits not only the proliferation of a non-CSC cancercell, but also cancer cell sphere-forming ability is possibly veryuseful as a novel antitumor agent.

(1) Non Patent Literature 2 describes the following compounds as quinonederivatives isolated from the extract of a plant of the Tabebuia genusin the Bignoniaceae family.

[wherein R¹, R², and R³ are hydrogen atoms; R¹ and R³ are H, R² is ahydroxyl group; R¹ is a hydroxyl group, R² and R³ and hydrogen atoms; R¹and R² and hydrogen atoms, and R³ is COCH₃; or R¹ and R² are hydrogenatoms, R³ is COC(CF₃)(OCH₃)C₆H₅.] It also discloses that these compoundshave antitumor activity.

(2) Patent Literature 1 describes the following compound havingantitumor activity and cancer cell sphere-forming ability.

[wherein X is O or S, R¹ is a hydrogen atom, a halogen atom, a cyanogroup, a nitro group, a trifluoromethyl group, a trifluoromethoxy group,an optionally substituted alkyl group, or the like, R³ is a hydrogenatom, a cyano group, an optionally substituted alkyl group, or the like,R⁷ is a hydrogen atom, a halogen atom, a cyano group, a nitro group, anoptionally substituted alkyl group, or the like, n is 1 to 4, with theproviso that when R³ is not an amino group, R⁷ is not a hydrogen atomand at least one of R¹ and R⁷ is a halogen atom, or an optionallysubstituted aryl group.]

Patent Literature 2 describes the following compound having antitumoractivity.

[wherein R¹, R², R³, R⁴, and R⁵ are the same as or different from oneanother, and are a hydrogen atom, an alkyl group, an alkenyl group, anaryl group, or a substituent having a nitrogen atom, an oxygen atom, asulfur atom, a phosphorus atom, or a halogen atom.]

Patent Literature 3 describes the following compound having antifungalactivity.

[wherein R¹ is a nitro group, an amino group, a cyano group, an alkylgroup, a halogen atom, or the like, R² is a hydrogen atom, a halogenatom, a short-chain alkyl group, a substituted aryl group, amethacrylate group, or the like, and the ring A is pyridine, isoxazole,or aryl.]

Non Patent Literature 3 describes the following compounds havingantitumor activity.

However, None of Non Patent Literatures 5 and 6 and Patent Literatures1-3 describes any specific compound represented by formula (1) of thepresent invention.

CITATION LIST Patent Literature

-   [Patent Literature 1]: International Publication No. 2009/036059    pamphlet-   [Patent Literature 2]: Japanese Laid-Open Publication No.    2002-284684-   [Patent Literature 3]: Chinese Patent Publication No. 103265559

Non Patent Literature

-   [Non Patent Literature 1]: Ponti et al. Cancer Res 65(13):5506-11.    2005-   [Non Patent Literature 2]: Rao et al. J Nat Prod 45(5):600-4. 1982-   [Non Patent Literature 3]: Koyama et al. Molecules 15(9):6559-69.    2010

SUMMARY OF INVENTION Technical Problem

The problem of the present invention is to provide significantly usefulcompound as a novel antitumor agent by providing a compound that istargeted to CSC, which is important in continuous proliferation of amalignant tumor, metastasis and recurrence of cancer, and its resistanceto an antitumor agent, and the compound inhibits not only theproliferation of non-CSC cancer cell but also cancer cell sphere-formingability.

Solution to Problem

The present inventors focused on quinone derivatives, and intensivelystudied with regard to their antitumor activities to find that acompound represented by the following formula (1) or a pharmacologicallyacceptable salt thereof (hereinafter also referred to as “the presentcompound”) has excellent effects on the inhibition of the proliferationof a cancer cell and cancer cell sphere-forming ability, and issignificantly useful as a novel antitumor agent. The present inventorsfinally reached the completion of the present invention.

Specifically, the present invention is as described below.

Item 1: A compound represented by formula (1) or a pharmacologicallyacceptable salt thereof:

wherein

A is O, S, or N—R⁶;

the ring G is a 5- or 6-membered aromatic ring that contains one tothree heteroatoms consisting of O, S, and N as constituent atoms;R¹ is each independently a hydrogen atom, a halogen atom, a cyano group,an optionally substituted 3- to 8-membered cyclic amino group, anoptionally substituted C₁₋₆ alkyl group (with the proviso that anunsubstituted methyl group, and a C₁₋₆ alkyl group substituted with onedimethyl amino group or one chlorine atom are excluded), an optionallysubstituted C₃₋₁₀ cycloalkyl group, an optionally substituted C₁₋₆alkenyl group, an optionally substituted C₁₋₆ alkynyl group, anoptionally substituted C₆₋₁₀ aryl group, an optionally substituted 5- to12-membered monocyclic or polycyclic heterocyclic group, an optionallysubstituted C₁₋₆ alkylcarbonyl group, an optionally substituted C₃₋₁₀cycloalkylcarbonyl group, an optionally substituted C₆₋₁₀ arylcarbonylgroup, an optionally substituted 5- to 12-membered monocyclic orpolycyclic heterocyclylcarbonyl group, a carboxyl group, an optionallysubstituted C₃₋₁₀ cycloalkyloxycarbonyl group, an optionally substitutedC₆₋₁₀ aryloxycarbonyl group, an optionally substituted 5- to 12-memberedmonocyclic or polycyclic heterocyclyloxycarbonyl group, an optionallysubstituted aminocarbonyl group, an optionally substituted 3- to8-membered cyclic aminocarbonyl group, an optionally substituted C₁₋₆alkylthio group, an optionally substituted C₃₋₁₀ cycloalkylthio group,an optionally substituted C₆₋₁₀ arylthio group, an optionallysubstituted 5- to 12-membered monocyclic or polycyclic heterocyclylthiogroup, a sulfinate group, an optionally substituted C₁₋₆ alkylsulfinylgroup, an optionally substituted C₃₋₁₀ cycloalkylsulfinyl group, anoptionally substituted C₆₋₁₀ arylsulfinyl group, an optionallysubstituted 5- to 12-membered monocyclic or polycyclicheterocyclylsulfinyl group, an optionally substituted aminosulfinylgroup, an optionally substituted 3- to 8-membered cyclic aminosulfinylgroup, a sulfonate group, an optionally substituted C₁₋₆ alkylsulfonylgroup, an optionally substituted C₃₋₁₀ cycloalkylsulfonyl group, anoptionally substituted C₆₋₁₀ arylsulfonyl group, an optionallysubstituted 5- to 12-membered monocyclic or polycyclicheterocyclylsulfonyl group, an optionally substituted aminosulfonylgroup, or an optionally substituted 3- to 8-membered cyclicaminosulfonyl group;R² is each independently a hydrogen atom, a halogen atom, a cyano group,a substituted amino group, an optionally substituted 3- to 8-memberedcyclic amino group, an optionally substituted C₁₋₆ alkyl group (with theproviso that an unsubstituted methyl group is excluded), an optionallysubstituted C₃₋₁₀ cycloalkyl group, an optionally substituted C₁₋₆alkenyl group, an optionally substituted C₁₋₆ alkynyl group, anoptionally substituted C₆₋₁₀ aryl group, an optionally substituted 5- to12-membered monocyclic or polycyclic heterocyclic group, an optionallysubstituted C₁₋₆ alkylcarbonyl group, an optionally substituted C₃₋₁₀cycloalkylcarbonyl group, an optionally substituted C₆₋₁₀ arylcarbonylgroup, an optionally substituted 5- to 12-membered monocyclic orpolycyclic heterocyclylcarbonyl group, a carboxyl group, an optionallysubstituted C₃₋₁₀ cycloalkyloxycarbonyl group, an optionally substitutedC₆₋₁₀ aryloxycarbonyl group, an optionally substituted 5- to 12-memberedmonocyclic or polycyclic heterocyclyloxycarbonyl group, an optionallysubstituted aminocarbonyl group, an optionally substituted 3- to8-membered cyclic aminocarbonyl group, an optionally substituted C₁₋₆alkylthio group, an optionally substituted C₃₋₁₀ cycloalkylthio group,an optionally substituted C₆₋₁₀ arylthio group, an optionallysubstituted 5- to 12-membered monocyclic or polycyclic heterocyclylthiogroup, a sulfinate group, an optionally substituted C₁₋₆ alkylsulfinylgroup, an optionally substituted C₃₋₁₀ cycloalkylsulfinyl group, anoptionally substituted C₆₋₁₀ arylsulfinyl group, an optionallysubstituted 5- to 12-membered monocyclic or polycyclicheterocyclylsulfinyl group, an optionally substituted aminosulfinylgroup, an optionally substituted 3- to 8-membered cyclic aminosulfinylgroup, a sulfonate group, an optionally substituted C₁₋₆ alkylsulfonylgroup, an optionally substituted C₃₋₁₀ cycloalkylsulfonyl group, anoptionally substituted C₆₋₁₀ arylsulfonyl group, an optionallysubstituted 5- to 12-membered monocyclic or polycyclicheterocyclylsulfonyl group, an optionally substituted aminosulfonylgroup, or an optionally substituted 3- to 8-membered cyclicaminosulfonyl group;R³, R⁴, or R⁵ is each independently a hydrogen atom, a halogen atom, acyano group, a hydroxyl group, an optionally substituted amino group, anoptionally substituted C₁₋₆ alkyl group, an optionally substituted C₃₋₁₀cycloalkyl group, an optionally substituted C₁₋₆ alkenyl group, anoptionally substituted C₁₋₆ alkynyl group, an optionally substitutedC₁₋₆ alkoxy group, an optionally substituted C₆₋₁₀ aryl group, anoptionally substituted 5- to 12-membered monocyclic or polycyclicheterocyclic group, an optionally substituted C₁₋₆ alkylcarbonyl group,an optionally substituted C₃₋₁₀ cycloalkylcarbonyl group, an optionallysubstituted C₆₋₁₀ arylcarbonyl group, an optionally substituted 5- to12-membered monocyclic or polycyclic heterocyclylcarbonyl group, acarboxyl group, an optionally substituted C₁₋₆ alkoxycarbonyl group, anoptionally substituted C₃₋₁₀ cycloalkyloxycarbonyl group, an optionallysubstituted C₆₋₁₀ aryloxycarbonyl group, an optionally substituted 5- to12-membered monocyclic or polycyclic heterocyclyloxycarbonyl group, anoptionally substituted aminocarbonyl group, an optionally substitutedC₁₋₆ alkylthio group, an optionally substituted C₃₋₁₀ cycloalkylthiogroup, an optionally substituted C₆₋₁₀ arylthio group, an optionallysubstituted 5- to 12-membered monocyclic or polycyclic heterocyclylthiogroup, a sulfinate group, an optionally substituted C₁₋₆ alkylsulfinylgroup, an optionally substituted C₃₋₁₀ cycloalkylsulfinyl group, anoptionally substituted C₆₋₁₀ arylsulfinyl group, an optionallysubstituted 5- to 12-membered monocyclic or polycyclicheterocyclylsulfinyl group, an optionally substituted aminosulfinylgroup, a sulfonate group, an optionally substituted C₁₋₆ alkylsulfonylgroup, an optionally substituted C₃₋₁₀ cycloalkylsulfonyl group, anoptionally substituted C₆₋₁₀ arylsulfonyl group, an optionallysubstituted 5- to 12-membered monocyclic or polycyclicheterocyclylsulfonyl group, or an optionally substituted aminosulfonylgroup;R⁶ is a hydrogen atom, an optionally substituted C₁₋₆ alkyl group, anoptionally substituted C₃₋₁₀ cycloalkyl group, an optionally substitutedC₆₋₁₀ aryl group, an optionally substituted 5- to 12-membered monocyclicor polycyclic heterocyclic group, an optionally substituted C₁₋₆alkylcarbonyl group, an optionally substituted C₃₋₁₀ cycloalkylcarbonylgroup, an optionally substituted C₆₋₁₀ arylcarbonyl group, an optionallysubstituted 5- to 12-membered monocyclic or polycyclicheterocyclylcarbonyl group, an optionally substituted C₁₋₆alkoxycarbonyl group, an optionally substituted C₃₋₁₀cycloalkyloxycarbonyl group, an optionally substituted C₆₋₁₀aryloxycarbonyl group, an optionally substituted 5- to 12-memberedmonocyclic or polycyclic heterocyclyloxycarbonyl group, an optionallysubstituted C₁₋₆ alkylsulfinyl group, an optionally substituted C₃₋₁₀cycloalkylsulfinyl group, an optionally substituted C₆₋₁₀ arylsulfinylgroup, an optionally substituted 5- to 12-membered monocyclic orpolycyclic heterocyclylsulfinyl group, an optionally substituted C₁₋₆alkylsulfonyl group, an optionally substituted C₃₋₁₀ cycloalkylsulfonylgroup, an optionally substituted C₆₋₁₀ arylsulfonyl group, or anoptionally substituted 5- to 12-membered monocyclic or polycyclicheterocyclylsulfonyl group; with the proviso that in the formula (1), acompound in which R¹ and R² are both hydrogen atoms,a compound in which when A is O, the ring G is a furan ring or animidazole ring,a compound in which when A is S, the ring G is a thiophene ring or animidazole ring,a compound in which when A is N—R⁶, the ring G is a pyrrole ring, apyrazole ring, or an imidazole ring,2-isopropylfuro[3,2-g]quinoline-4,9-dione, and ethyl4,8-dioxo-2,7-diphenyl-4,8-dihydrothieno[2,3-f]benzofuran-6-carboxylateare excluded.Item 2: The compound according to item 1 or a pharmacologicallyacceptable salt thereof, wherein A is S.Item 3: The compound according to item 1 or a pharmacologicallyacceptable salt thereof, wherein A is O.Item 4: The compound according to item 1 or a pharmacologicallyacceptable salt thereof, wherein A is N—R⁶.Item 5: The compound according to any one of items 1-4 or apharmacologically acceptable salt thereof, wherein the ring G is of anyformula selected from the group consisting of the following formulas (a)to (l):

Item 6: The compound according to item 5 or a pharmacologicallyacceptable salt thereof, wherein the ring G is of any formula selectedfrom the group consisting of the following formulas (a) to (h):

Item 7: The compound according to item 6 or a pharmacologicallyacceptable salt thereof, wherein the ring G is of any formula selectedfrom the group consisting of the following formulas (a) to (f):

Item 8: The compound according to item 7 or a pharmacologicallyacceptable salt thereof, wherein the ring G is of any formula selectedfrom the group consisting of the following formulas (b) or (e):

Item 9: The compound according to any one of items 1-8 or apharmacologically acceptable salt thereof, wherein R¹ is a groupselected from the group consisting of:1: a hydrogen atom;2: a cyano group;3: a C₁₋₆ alkyl group (wherein the alkyl is optionally substituted withone to three groups selected from the group consisting of a fluorineatom, hydroxy, C₁₋₆ alkoxy, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, and 3- to8-membered cyclic amino);4: a C₁₋₆ alkylcarbonyl group (wherein the alkyl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, amino (which is optionally substituted withone or two C₁₋₆ alkyl groups), C₁₋₆ alkoxy, C₃₋₁₀ cycloalkyl, C₆₋₁₀aryl, and a 5- to 12-membered monocyclic or polycyclic heterocycle(which is optionally substituted with one to three C₁₋₆ alkyl));5: a C₆₋₁₀ aryl group (wherein the aryl is optionally substituted one tothree groups selected from a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆alkoxy);6: a 5- to 12-membered monocyclic or polycyclic heterocyclic group(wherein the heterocycle is optionally substituted with one to threegroups selected from the group consisting of a halogen atom, hydroxy,C₁₋₆ alkyl, and C₁₋₆ alkoxy);7: a carboxyl group;8: an aminocarbonyl group (wherein the amino is optionally substitutedwith one or two groups selected from the group consisting of(a) C₁₋₆ alkyl (wherein the alkyl is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₄ alkoxy, C₆₋₁₀ aryl, and a 5- to 12-membered monocyclic orpolycyclic heterocycle (which is optionally substituted with one tothree C₁₋₆ alkyl)),(b) C₃₋₁₀ cycloalkyl (wherein the cycloalkyl is optionally substitutedwith one to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy),(c) C₆₋₁₀ aryl (wherein the aryl is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₆ alkyl, or C₁₋₆ alkoxy), and(d) a 5- to 12-membered monocyclic or polycyclic heterocycle (whereinthe heterocycle is optionally substituted with one to three groupsselected from a halogen atom, hydroxy, C₁₋₆ alkyl, or C₁₋₆ alkoxy)); and9: a 3- to 8-membered cyclic aminocarbonyl group (wherein the cyclicamino is optionally substituted with one to three C₁₋₆ alkyl).Item 10: The compound according to item 9 or a pharmacologicallyacceptable salt thereof, wherein R¹ is a hydrogen atom or a C₁₋₆alkylcarbonyl group (wherein the alkyl is optionally substituted with 3-to 8-membered cyclic amino).Item 11: The compound according to any one of items 1-10 or apharmacologically acceptable salt thereof, wherein R² is a groupselected from the group consisting of:1: a hydrogen atom;2: a halogen atom;3: a cyano group;4: an amino group (wherein the amino is substituted with one or twogroups selected from the group consisting of(a) C₁₋₆ alkyl (wherein the alkyl is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₄ alkoxy, C₆₋₁₀ aryl, and a 5- to 12-membered monocyclic orpolycyclic heterocycle (which is optionally substituted with one tothree C₁₋₆ alkyl)),(b) C₁₋₆ alkylcarbonyl (wherein the alkyl is optionally substituted withone to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₄ alkoxy, C₆₋₁₀ aryl, and a 5- to 12-memberedmonocyclic or polycyclic heterocycle (which is optionally substitutedwith one to three C₁₋₆ alkyl)),(c) C₃₋₁₀ cycloalkyl (wherein the cycloalkyl is optionally substitutedwith one to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy),(d) C₆₋₁₀ aryl (wherein the aryl is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy), and(e) a 5- to 12-membered monocyclic or polycyclic heterocycle (whereinthe heterocycle is optionally substituted with one to three groupsselected from the group consisting of a halogen atom, hydroxy, C₁₋₆alkyl, and C₁₋₆ alkoxy));5: a 3- to 8-membered cyclic amino group (wherein the cyclic amino isoptionally substituted with one to three C₁₋₆ alkyl);6: a C₁₋₆ alkyl group (wherein the alkyl is optionally substituted withone to three groups selected from the group consisting of(a) a halogen atom,(b) hydroxy,(c) amino (wherein the amino is optionally substituted with one or twogroups selected from the group consisting of(i) C₁₋₆ alkyl (wherein the alkyl is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₄ alkoxy, an aminocarbonyl group (wherein the amino isoptionally substituted with one to three C₁₋₆ alkyl), C₆₋₁₀ aryl, and a5- to 12-membered monocyclic or polycyclic heterocycle (which isoptionally substituted with one to three C₁₋₆ alkyl))),(ii) C₃₋₈ cycloalkyl (wherein the cycloalkyl is optionally substitutedwith one to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₆ alkyl, or C₁₋₆ alkoxy),(iii) C₁₋₆ alkylcarbonyl (wherein the alkyl is optionally substitutedwith one to three groups selected from a halogen atom, hydroxy, C₁₋₄alkoxy, C₆₋₁₀ aryl, or a 5- to 12-membered monocyclic or polycyclicheterocycle (which is optionally substituted with one to three C₁₋₆alkyl)),(iv) C₁₋₆ alkoxycarbonyl (wherein the alkyl is optionally substitutedwith one to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₄ alkoxy, C₆₋₁₀ aryl, and a 5- to 12-memberedmonocyclic or polycyclic heterocycle (which is optionally substitutedwith one to three C₁₋₆ alkyl)),(v) C₁₋₆ alkylsulfinyl (wherein the alkyl is optionally substituted withone to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₄ alkoxy, C₆₋₁₀ aryl, and a 5- to 12-memberedmonocyclic or polycyclic heterocycle (which is optionally substitutedwith one to three C₁₋₆ alkyl)),(vi) C₁₋₆ alkylsulfonyl (wherein the alkyl is optionally substitutedwith one to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₄ alkoxy, C₆₋₁₀ aryl, and a 5- to 12-memberedmonocyclic or polycyclic heterocycle (which is optionally substitutedwith one to three C₁₋₆ alkyl)),(vii) aminocarbonyl (wherein the amino is optionally substituted withone or two C₁₋₆ alkyl (wherein the alkyl is optionally substituted withone to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₄ alkoxy, C₆₋₁₀ aryl, and a 5- to 12-memberedmonocyclic or polycyclic heterocycle (which is optionally substitutedwith one to three C₁₋₆ alkyl))),(viii) 3- to 8-membered cyclic amino (wherein the cyclic amino isoptionally substituted with one to three C₁₋₆ alkyl), and(ix) C₃₋₁₀ cycloalkylcarbonyl,(d) 3- to 8-membered cyclic amino (wherein the cyclic amino isoptionally substituted with one to three C₁₋₆ alkylcarbonyl),(e) C₁₋₆ alkoxy (wherein the alkoxy is optionally substituted with oneto three C₆₋₁₀ aryl),(f) C₃₋₁₀ cycloalkyl,(g) C₆₋₁₀ aryl, and(h) a 5- to 12-membered monocyclic or polycyclic heterocycle);7: a C₃₋₁₀ cycloalkyl group (wherein the cycloalkyl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);8: a C₁₋₆ alkenyl group (the alkenyl is optionally substituted with oneto three groups selected from C₁₋₆ alkyl and C₁₋₆ alkoxycarbonylgroups);9: a C₁₋₆ alkynyl group (the alkynyl is optionally substituted with oneto three groups selected from C₁₋₆ alkyl and C₁₋₆ alkoxycarbonylgroups);10: a C₆₋₁₀ aryl group (wherein the aryl is optionally substituted withone to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);11: a 5- to 12-membered monocyclic or polycyclic heterocyclic group(wherein the heterocycle is optionally substituted with one to threegroups selected from a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆alkoxy);12: a C₃₋₁₀ cycloalkyloxy group (wherein the cycloalkyl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);13: a C₆₋₁₀ aryloxy group (wherein the aryl is optionally substitutedwith one to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);14: a 5- to 12-membered monocyclic or polycyclic heterocyclyloxy group(wherein the heterocycle is optionally substituted with one to threegroups selected from the group consisting of a halogen atom, hydroxy,C₁₋₆ alkyl, and C₁₋₆ alkoxy);15: a carboxyl group;16: a C₁₋₆ alkylcarbonyl group (wherein the alkyl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, amino (which is optionally substituted withone or two C₁₋₆ alkyl groups), C₁₋₆ alkoxy, C₃₋₁₀ cycloalkyl, C₆₋₁₀aryl, and a 5- to 12-membered monocyclic or polycyclic heterocycle);17: a C₃₋₁₀ cycloalkylcarbonyl group (wherein the cycloalkyl isoptionally substituted with one to three groups selected from the groupconsisting of a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);18: a C₆₋₁₀ arylcarbonyl group (wherein the aryl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);19: a 5- to 12-membered monocyclic or polycyclic heterocyclylcarbonylgroup (wherein the heterocycle is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);20: a C₃₋₁₀ cycloalkyloxycarbonyl group (wherein the cycloalkyl isoptionally substituted with one to three groups selected from the groupconsisting of a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);21: a C₆₋₁₀ aryloxycarbonyl group (wherein the aryl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);22: a 5- to 12-membered monocyclic or polycyclic heterocyclyloxycarbonylgroup (wherein the heterocycle is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);23: an aminocarbonyl group (wherein the amino is optionally substitutedwith one or two groups selected from(a) C₁₋₆ alkyl (wherein the alkyl is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₄ alkoxy, C₆₋₁₀ aryl, and a 5- to 12-membered monocyclic orpolycyclic heterocycle (which is optionally substituted with one tothree C₁₋₆ alkyl)),(b) C₃₋₁₀ cycloalkyl (wherein the cycloalkyl is optionally substitutedwith one to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy),(c) C₆₋₁₀ aryl (wherein the aryl is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy), and(d) a 5- to 12-membered monocyclic or polycyclic heterocycle (whereinthe heterocycle is optionally substituted with one to three groupsselected from the group consisting of a halogen atom, hydroxy, C₁₋₆alkyl, and C₁₋₆ alkoxy));24: a 3- to 8-membered cyclic aminocarbonyl group (wherein the cyclicamino is optionally substituted with one to three C₁₋₆ alkyl);25: a C₁₋₆ alkylthio group (wherein the alkyl is optionally substitutedwith one to three groups selected from the group consisting of a halogenatom, hydroxy, amino (which is optionally substituted with one or twoC₁₋₆ alkyl groups), C₁₋₆ alkoxy, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, and a 5-to 12-membered monocyclic or polycyclic heterocycle);26: a C₃₋₁₀ cycloalkylthio group (wherein the cycloalkyl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);27: a C₆₋₁₀ arylthio group (wherein the aryl is optionally substitutedwith one to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);28: a 5- to 12-membered monocyclic or polycyclic heterocyclylthio group(wherein the heterocycle is optionally substituted with one to threegroups selected from the group consisting of a halogen atom, hydroxy,C₁₋₆ alkyl, and C₁₋₆ alkoxy);29: a sulfinate group;30: a C₁₋₆ alkylsulfinyl group (wherein the alkyl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, amino (which is optionally substituted withone or two C₁₋₆ alkyl groups), C₁₋₆ alkoxy, C₃₋₁₀ cycloalkyl, C₆₋₁₀aryl, and a 5- to 12-membered monocyclic or polycyclic heterocycle);31: a C₃₋₁₀ cycloalkylsulfinyl group (wherein the cycloalkyl isoptionally substituted with one to three groups selected from the groupconsisting of a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);32: a C₆₋₁₀ arylsulfinyl group (wherein the aryl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);33: a 5- to 12-membered monocyclic or polycyclic heterocyclylsulfinylgroup (wherein the heterocycle is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);34: an aminosulfinyl group (wherein the amino is optionally substitutedwith one or two groups selected from the group consisting of(a) C₁₋₆ alkyl (wherein the alkyl is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₄ alkoxy, C₆₋₁₀ aryl, and a 5- to 12-membered monocyclic orpolycyclic heterocycle (which is optionally substituted with one tothree C₁₋₆ alkyl)),(b) C₃₋₁₀ cycloalkyl (wherein the cycloalkyl is optionally substitutedwith one to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy),(c) C₆₋₁₀ aryl (wherein the aryl is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy), and(d) a 5- to 12-membered monocyclic or polycyclic heterocycle (whereinthe heterocycle is optionally substituted with one to three groupsselected from the group consisting of a halogen atom, hydroxy, C₁₋₆alkyl, and C₁₋₆ alkoxy));35: a 3- to 8-membered cyclic aminosulfinyl group (wherein the cyclicamino is optionally substituted with one to three C₁₋₆ alkyl);36: a sulfonate group;37: a C₁₋₆ alkylsulfonyl group (wherein the alkyl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, amino (which is optionally substituted withone or two C₁₋₆ alkyl groups), C₁₋₆ alkoxy, C₃₋₁₀ cycloalkyl, C₆₋₁₀aryl, and a 5- to 12-membered monocyclic or polycyclic heterocycle);38: a C₃₋₁₀ cycloalkylsulfonyl group (wherein the cycloalkyl isoptionally substituted with one to three groups selected from the groupconsisting of a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);39: a C₆₋₁₀ arylsulfonyl group (wherein the aryl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);40: a 5- to 12-membered monocyclic or polycyclic heterocyclylsulfonylgroup (wherein the heterocycle is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);41: an aminosulfonyl group (wherein the amino is optionally substitutedwith one or two groups selected from the group consisting of(a) C₁₋₆ alkyl (wherein the alkyl is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₄ alkoxy, C₆₋₁₀ aryl, and a 5- to 12-membered monocyclic orpolycyclic heterocycle (which is optionally substituted with one tothree C₁₋₆ alkyl)),(b) C₃₋₁₀ cycloalkyl (wherein the cycloalkyl is optionally substitutedwith one to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy),(c) C₆₋₁₀ aryl (wherein the aryl is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy), and(d) a 5- to 12-membered monocyclic or polycyclic heterocycle (whereinthe heterocycle is optionally substituted with one to three groupsselected from the group consisting of a halogen atom, hydroxy, C₁₋₆alkyl, and C₁₋₆ alkoxy)); and42: a 3- to 8-membered cyclic aminosulfinyl group (wherein the cyclicamino is optionally substituted with one to three C₁₋₆ alkyl).Item 12: The compound according to any one of items 1-11 or apharmacologically acceptable salt thereof, wherein R² is a groupselected from the group consisting of:1: a hydrogen atom;2: a halogen atom;3: a cyano group;4: an amino group (wherein the amino is substituted with one or twogroups selected from the group consisting of(a) C₁₋₆ alkyl (wherein the alkyl is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₄ alkoxy, C₆₋₁₀ aryl, and a 5- to 12-membered monocyclic orpolycyclic heterocycle (which is optionally substituted with one tothree C₁₋₆ alkyl)),(b) C₁₋₆ alkylcarbonyl (wherein the alkyl is optionally substituted withone to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₄ alkoxy, C₆₋₁₀ aryl, and a 5- to 12-memberedmonocyclic or polycyclic heterocycle (which is optionally substitutedwith one to three C₁₋₆ alkyl)),(c) C₃₋₁₀ cycloalkyl (wherein the cycloalkyl is optionally substitutedwith one to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy),(d) C₆₋₁₀ aryl (wherein the aryl is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy), and(e) a 5- to 12-membered monocyclic or polycyclic heterocycle (whereinthe heterocycle is optionally substituted with one to three groupsselected from the group consisting of a halogen atom, hydroxy, C₁₋₆alkyl, and C₁₋₆ alkoxy));5: a 3- to 8-membered cyclic amino group (wherein the cyclic amino isoptionally substituted with one to three C₁₋₆ alkyl);6: a C₁₋₆ alkyl group (wherein the alkyl is optionally substituted withone to three groups selected from the group consisting of(a) a halogen atom,(b) hydroxy,(c) amino (wherein the amino is optionally substituted with one or twogroups selected from the group consisting of(i) C₁₋₆ alkyl (wherein the alkyl is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₄ alkoxy, C₆₋₁₀ aryl, and a 5- to 12-membered monocyclic orpolycyclic heterocycle (which is optionally substituted with one tothree C₁₋₆ alkyl)),(ii) C₃₋₈ cycloalkyl (wherein the cycloalkyl is optionally substitutedwith one to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₆ alkyl, or C₁₋₆ alkoxy),(iii) C₁₋₆ alkylcarbonyl (wherein the alkyl is optionally substitutedwith one to three groups selected from a halogen atom, hydroxy, C₁₋₄alkoxy, C₆₋₁₀ aryl, or a 5- to 12-membered monocyclic or polycyclicheterocycle (which is optionally substituted with one to three C₁₋₆alkyl)),(iv) C₁₋₆ alkoxycarbonyl (wherein the alkyl is optionally substitutedwith one to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₄ alkoxy, C₆₋₁₀ aryl, and a 5- to 12-memberedmonocyclic or polycyclic heterocycle (which is optionally substitutedwith one to three C₁₋₆ alkyl)),(v) C₁₋₆ alkylsulfinyl (wherein the alkyl is optionally substituted withone to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₄ alkoxy, C₆₋₁₀ aryl, and a 5- to 12-memberedmonocyclic or polycyclic heterocycle (which is optionally substitutedwith one to three C₁₋₆ alkyl)),(vi) C₁₋₆ alkylsulfonyl (wherein the alkyl is optionally substitutedwith one to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₄ alkoxy, C₆₋₁₀ aryl, and a 5- to 12-memberedmonocyclic or polycyclic heterocycle (which is optionally substitutedwith one to three C₁₋₆ alkyl)),(vii) aminocarbonyl (wherein the amino is optionally substituted withone or two C₁₋₆ alkyl (wherein the alkyl is optionally substituted withone to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₄ alkoxy, C₆₋₁₀ aryl, and a 5- to 12-memberedmonocyclic or polycyclic heterocycle (which is optionally substitutedwith one to three C₁₋₆ alkyl))), and(viii) 3- to 8-membered cyclic amino (wherein the cyclic amino isoptionally substituted with one to three C₁₋₆ alkyl)),(d) 3- to 8-membered cyclic amino,(e) C₁₋₆ alkoxy,(f) C₃₋₁₀ cycloalkyl,(g) C₆₋₁₀ aryl, and(h) a 5- to 12-membered monocyclic or polycyclic heterocycle);7: a C₃₋₁₀ cycloalkyl group (wherein the cycloalkyl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);8: a C₆₋₁₀ aryl group (wherein the aryl is optionally substituted withone to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);9: a 5- to 12-membered monocyclic or polycyclic heterocyclic group(wherein the heterocycle is optionally substituted with one to threegroups selected from a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆alkoxy);10: a C₃₋₁₀ cycloalkyloxy group (wherein the cycloalkyl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);11: a C₆₋₁₀ aryloxy group (wherein the aryl is optionally substitutedwith one to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);12: a 5- to 12-membered monocyclic or polycyclic heterocyclyloxy group(wherein the heterocycle is optionally substituted with one to threegroups selected from the group consisting of a halogen atom, hydroxy,C₁₋₆ alkyl, and C₁₋₆ alkoxy);13: a carboxyl group;14: a C₁₋₆ alkylcarbonyl group (wherein the alkyl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, amino (which is optionally substituted withone or two C₁₋₆ alkyl groups), C₁₋₆ alkoxy, C₃₋₁₀ cycloalkyl, C₆₋₁₀aryl, and a 5- to 12-membered monocyclic or polycyclic heterocycle);15: a C₃₋₁₀ cycloalkylcarbonyl group (wherein the cycloalkyl isoptionally substituted with one to three groups selected from the groupconsisting of a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);16: a C₆₋₁₀ arylcarbonyl group (wherein the aryl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);17: a 5- to 12-membered monocyclic or polycyclic heterocyclylcarbonylgroup (wherein the heterocycle is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);18: a C₃₋₁₀ cycloalkyloxycarbonyl group (wherein the cycloalkyl isoptionally substituted with one to three groups selected from the groupconsisting of a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);19: a C₆₋₁₀ aryloxycarbonyl group (wherein the aryl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);20: a 5- to 12-membered monocyclic or polycyclic heterocyclyloxycarbonylgroup (wherein the heterocycle is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);21: an aminocarbonyl group (wherein the amino is optionally substitutedwith one or two groups selected from(a) C₁₋₆ alkyl (wherein the alkyl is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₄ alkoxy, C₆₋₁₀ aryl, and a 5- to 12-membered monocyclic orpolycyclic heterocycle (which is optionally substituted with one tothree C₁₋₆ alkyl)),(b) C₃₋₁₀ cycloalkyl (wherein the cycloalkyl is optionally substitutedwith one to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy),(c) C₆₋₁₀ aryl (wherein the aryl is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy), and(d) a 5- to 12-membered monocyclic or polycyclic heterocycle (whereinthe heterocycle is optionally substituted with one to three groupsselected from the group consisting of a halogen atom, hydroxy, C₁₋₆alkyl, and C₁₋₆ alkoxy));22: a 3- to 8-membered cyclic aminocarbonyl group (wherein the cyclicamino is optionally substituted with one to three C₁₋₆ alkyl);23: a C₁₋₆ alkylthio group (wherein the alkyl is optionally substitutedwith one to three groups selected from the group consisting of a halogenatom, hydroxy, amino (which is optionally substituted with one or twoC₁₋₆ alkyl groups), C₁₋₆ alkoxy, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, and a 5-to 12-membered monocyclic or polycyclic heterocycle);24: a C₃₋₁₀ cycloalkylthio group (wherein the cycloalkyl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);25: a C₆₋₁₀ arylthio group (wherein the aryl is optionally substitutedwith one to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);26: a 5- to 12-membered monocyclic or polycyclic heterocyclylthio group(wherein the heterocycle is optionally substituted with one to threegroups selected from the group consisting of a halogen atom, hydroxy,C₁₋₆ alkyl, and C₁₋₆ alkoxy);27: a sulfinate group;28: a C₁₋₆ alkylsulfinyl group (wherein the alkyl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, amino (which is optionally substituted withone or two C₁₋₆ alkyl groups), C₁₋₆ alkoxy, C₃₋₁₀ cycloalkyl, C₆₋₁₀aryl, and a 5- to 12-membered monocyclic or polycyclic heterocycle);29: a C₃₋₁₀ cycloalkylsulfinyl group (wherein the cycloalkyl isoptionally substituted with one to three groups selected from the groupconsisting of a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);30: a C₆₋₁₀ arylsulfinyl group (wherein the aryl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);31: a 5- to 12-membered monocyclic or polycyclic heterocyclylsulfinylgroup (wherein the heterocycle is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);32: an aminosulfinyl group (wherein the amino is optionally substitutedwith one or two groups selected from the group consisting of(a) C₁₋₆ alkyl (wherein the alkyl is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₄ alkoxy, C₆₋₁₀ aryl, and a 5- to 12-membered monocyclic orpolycyclic heterocycle (which is optionally substituted with one tothree C₁₋₆ alkyl)),(b) C₃₋₁₀ cycloalkyl (wherein the cycloalkyl is optionally substitutedwith one to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy),(c) C₆₋₁₀ aryl (wherein the aryl is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy), and(d) a 5- to 12-membered monocyclic or polycyclic heterocycle (whereinthe heterocycle is optionally substituted with one to three groupsselected from the group consisting of a halogen atom, hydroxy, C₁₋₆alkyl, and C₁₋₆ alkoxy));33: a 3- to 8-membered cyclic aminosulfinyl group (wherein the cyclicamino is optionally substituted with one to three C₁₋₆ alkyl);34: a sulfonate group;35: a C₁₋₆ alkylsulfonyl group (wherein the alkyl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, amino (which is optionally substituted withone or two C₁₋₆ alkyl groups), C₁₋₆ alkoxy, C₃₋₁₀ cycloalkyl, C₆₋₁₀aryl, and a 5- to 12-membered monocyclic or polycyclic heterocycle);36: a C₃₋₁₀ cycloalkylsulfonyl group (wherein the cycloalkyl isoptionally substituted with one to three groups selected from the groupconsisting of a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);37: a C₆₋₁₀ arylsulfonyl group (wherein the aryl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);38: a 5- to 12-membered monocyclic or polycyclic heterocyclylsulfonylgroup (wherein the heterocycle is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);39: an aminosulfonyl group (wherein the amino is optionally substitutedwith one or two groups selected from the group consisting of(a) C₁₋₆ alkyl (wherein the alkyl is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₄ alkoxy, C₆₋₁₀ aryl, and a 5- to 12-membered monocyclic orpolycyclic heterocycle (which is optionally substituted with one tothree C₁₋₆ alkyl)),(b) C₃₋₁₀ cycloalkyl (wherein the cycloalkyl is optionally substitutedwith one to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy),(c) C₆₋₁₀ aryl (wherein the aryl is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy), and(d) a 5- to 12-membered monocyclic or polycyclic heterocycle (whereinthe heterocycle is optionally substituted with one to three groupsselected from the group consisting of a halogen atom, hydroxy, C₁₋₆alkyl, and C₁₋₆ alkoxy)); and40: a 3- to 8-membered cyclic aminosulfinyl group (wherein the cyclicamino is optionally substituted with one to three C₁₋₆ alkyl).Item 13: The compound according to any one of items 1-11 or apharmacologically acceptable salt thereof, wherein R² is a groupselected from the group consisting of:1: a hydrogen atom;2: a halogen atom;3: a cyano group;4: an amino group (wherein the amino is optionally substituted with oneto three C₁₋₆ alkyl groups);5: a 3- to 8-membered cyclic amino group (wherein the cyclic amino isoptionally substituted with one to three C₁₋₆ alkyl);6: a C₁₋₆ alkyl group (wherein the alkyl is optionally substituted withone to three groups selected from the group consisting of(a) a halogen atom,(b) hydroxy,(c) amino (wherein the amino is optionally substituted with one or twogroups selected from the group consisting of(i) C₁₋₆ alkyl (wherein the alkyl is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, and C₁₋₄ alkoxy),(ii) C₃₋₈ cycloalkyl,(iii) C₁₋₆ alkylcarbonyl,(iv) C₁₋₆ alkoxycarbonyl, and(v) C₁₋₆ alkylsulfonyl),(d) 3- to 8-membered cyclic amino,(e) C₁₋₆ alkoxy,(f) C₃₋₁₀ cycloalkyl,(g) phenyl, and(h) a 5- to 6-membered monocyclic or polycyclic heterocycle);7: a C₁₋₆ alkenyl group (wherein the alkenyl is optionally substitutedwith one to three groups selected from C₁₋₆ alkyl and C₁₋₆alkoxycarbonyl groups);8: a C₁₋₆ alkynyl group (wherein the alkynyl is optionally substitutedwith one to three groups selected from C₁₋₆ alkyl and C₁₋₆alkoxycarbonyl groups);9: a 5- to 12-membered monocyclic or polycyclic heterocyclic group;10: a C₁₋₆ alkylcarbonyl group (wherein the alkyl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, amino (which is optionally substituted withone or two C₁₋₆ alkyl groups), C₁₋₄ alkoxy, C₃₋₈ cycloalkyl, phenyl, anda 5- to 6-membered monocyclic heterocycle (which is optionallysubstituted with one to three C₁₋₆ alkyl));11: an aminocarbonyl group (wherein the amino is(a) C₁₋₆ alkyl (wherein the alkyl is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₄ alkoxy, phenyl, and a 5- to 6-membered monocyclicheterocycle (which is optionally substituted with one to three C₁₋₄alkyl)),(b) C₃₋₈ cycloalkyl (wherein the cycloalkyl is optionally substitutedwith one to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy),(c) phenyl (wherein the aryl is optionally substituted with one to threegroups selected from the group consisting of a halogen atom, hydroxy,C₁₋₆ alkyl, and C₁₋₆ alkoxy), and(d) a 5- to 6-membered monocyclic heterocycle (wherein the heterocycleis optionally substituted with one to three groups selected from thegroup consisting of a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆alkoxy)); and12: a 3- to 8-membered cyclic aminocarbonyl group (wherein the cyclicamino is optionally substituted with one to three C₁₋₆ alkyl).Item 14: The compound according to item 13 or a pharmacologicallyacceptable salt thereof, wherein R² is a group selected from the groupconsisting of:1: a C₁₋₆ alkyl group (wherein the alkyl is optionally substituted withone to three groups selected from the group consisting of a halogenatom, hydroxy, amino (which is optionally substituted with one or twoC₁₋₆ alkyl groups), C₁₋₄ alkoxy, C₃₋₈ cycloalkyl, phenyl, and a 5- to6-membered monocyclic heterocycle);2: a C₁₋₆ alkylcarbonyl group (wherein the alkyl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, amino (which is optionally substituted withone or two C₁₋₆ alkyl groups), C₁₋₄ alkoxy, C₃₋₈ cycloalkyl, phenyl, anda 5- to 6-membered monocyclic heterocycle (which is optionallysubstituted with one to three C₁₋₆ alkyl));3: an aminocarbonyl group (wherein the amino is optionally substitutedwith one or two groups selected from(a) C₁₋₆ alkyl (wherein the alkyl is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₄ alkoxy, phenyl, and a 5- to 6-membered monocyclicheterocycle (which is optionally substituted with one to three C₁₋₄alkyl)),(b) C₃₋₈ cycloalkyl (wherein the cycloalkyl is optionally substitutedwith one to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy),(c) phenyl (wherein the aryl is optionally substituted with one to threegroups selected from the group consisting of a halogen atom, hydroxy,C₁₋₆ alkyl, and C₁₋₆ alkoxy), and(d) a 5- to 6-membered monocyclic heterocycle (wherein the heterocycleis optionally substituted with one to three groups selected from thegroup consisting of a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆alkoxy)); and4: a 3- to 8-membered cyclic aminocarbonyl group (wherein the cyclicamino is optionally substituted with one to three C₁₋₆ alkyl).Item 15: The compound according to any one of items 1-14 or apharmacologically acceptable salt thereof, whereinR³, R⁴, or R⁵ is each independently a group selected from the groupconsisting of:1: a hydrogen atom;2: a halogen atom;3: a cyano group;4: a hydroxyl group;5: an amino group (wherein the amino is optionally substituted with oneor two groups selected from the group consisting of(a) C₁₋₆ alkyl (wherein the alkyl is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₄ alkoxy, C₆₋₁₀ aryl, and a 5- to 12-membered monocyclic orpolycyclic heterocycle (which is optionally substituted with one tothree C₁₋₆ alkyl)),(b) C₁₋₆ alkylcarbonyl (wherein the alkyl is optionally substituted withone to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₄ alkoxy, C₆₋₁₀ aryl, and a 5- to 12-memberedmonocyclic or polycyclic heterocycle (which is optionally substitutedwith one to three C₁₋₆ alkyl)),(c) C₃₋₁₀ cycloalkyl (wherein the cycloalkyl is optionally substitutedwith one to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy),(d) C₆₋₁₀ aryl (wherein the aryl is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy), and(e) a 5- to 12-membered monocyclic or polycyclic heterocycle (whereinthe heterocycle is optionally substituted with one to three groupsselected from the group consisting of a halogen atom, hydroxy, C₁₋₆alkyl, and C₁₋₆ alkoxy));6: a 3- to 8-membered cyclic amino group (wherein the cyclic amino isoptionally substituted with one to three C₁₋₆ alkyl);7: a C₁₋₆ alkyl group (wherein the alkyl is optionally substituted withone to three groups selected from a halogen atom, hydroxy, amino (whichis optionally substituted with one or two C₁₋₆ alkyl), C₁₋₆ alkoxy,C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, and a 5- to 12-membered monocyclic orpolycyclic heterocycle);8: a C₃₋₁₀ cycloalkyl group (wherein the cycloalkyl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);9: a C₆₋₁₀ aryl group (wherein the aryl is optionally substituted withone to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);10: a 5- to 12-membered monocyclic or polycyclic heterocyclic group(wherein the heterocycle is optionally substituted with one to threegroups selected from the group consisting of a halogen atom, hydroxy,C₁₋₆ alkyl, and C₁₋₆ alkoxy);11: a C₁₋₆ alkoxy group (wherein the alkyl is optionally substitutedwith one to three groups selected from the group consisting of a halogenatom, hydroxy, amino (which is optionally substituted with one or twoC₁₋₆ alkyl groups), C₁₋₆ alkoxy, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, and a 5-to 12-membered monocyclic or polycyclic heterocycle);12: a C₃₋₁₀ cycloalkyloxy group (wherein the cycloalkyl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);13: a C₆₋₁₀ aryloxy group (wherein the aryl is optionally substitutedwith one to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);14: a 5- to 12-membered monocyclic or polycyclic heterocyclyloxy group(wherein the heterocycle is optionally substituted with one to threegroups selected from the group consisting of a halogen atom, hydroxy,C₁₋₆ alkyl, and C₁₋₆ alkoxy);15: a carboxyl group;16: a C₁₋₆ alkylcarbonyl group (wherein the alkyl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, amino (which is optionally substituted withone or two C₁₋₆ alkyl groups), C₁₋₆ alkoxy, C₃₋₁₀ cycloalkyl, C₆₋₁₀aryl, and a 5- to 12-membered monocyclic or polycyclic heterocycle);17: a C₃₋₁₀ cycloalkylcarbonyl group (wherein the cycloalkyl isoptionally substituted with one to three groups selected from the groupconsisting of a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);18: a C₆₋₁₀ arylcarbonyl group (wherein the aryl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);19: a 5- to 12-membered monocyclic or polycyclic heterocyclylcarbonylgroup (wherein the heterocycle is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);20: a C₁₋₆ alkoxycarbonyl group (wherein the alkyl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, amino (which is optionally substituted withone or two C₁₋₆ alkyl groups), C₁₋₆ alkoxy, C₃₋₁₀ cycloalkyl, C₆₋₁₀aryl, and a 5- to 12-membered monocyclic or polycyclic heterocycle);21: a C₃₋₁₀ cycloalkyloxycarbonyl group (wherein the cycloalkyl isoptionally substituted with one to three groups selected from the groupconsisting of a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);22: a C₆₋₁₀ aryloxycarbonyl group (wherein the aryl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);23: a 5- to 12-membered monocyclic or polycyclic heterocyclyloxycarbonylgroup (wherein the heterocycle is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);24: an aminocarbonyl group (wherein the amino is optionally substitutedwith one or two groups selected from the group consisting of(a) C₁₋₆ alkyl (wherein the alkyl is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₄ alkoxy, C₆₋₁₀ aryl, and a 5- to 12-membered monocyclic orpolycyclic heterocycle (which is optionally substituted with one tothree C₁₋₆ alkyl)),(b) C₃₋₁₀ cycloalkyl (wherein the cycloalkyl is optionally substitutedwith one to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy),(c) C₆₋₁₀ aryl (wherein the aryl is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy), and(d) a 5- to 12-membered monocyclic or polycyclic heterocycle (whereinthe heterocycle is optionally substituted with one to three groupsselected from the group consisting of a halogen atom, hydroxy, C₁₋₆alkyl, and C₁₋₆ alkoxy));25: a 3- to 8-membered cyclic aminocarbonyl group (wherein the cyclicamino is optionally substituted with one to three C₁₋₆ alkyl);26: a C₁₋₆ alkylthio group (wherein the alkyl is optionally substitutedwith one to three groups selected from the group consisting of a halogenatom, hydroxy, amino (which is optionally substituted with one or twoC₁₋₆ alkyl), C₁₋₆ alkoxy, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, and a 5- to12-membered monocyclic or polycyclic heterocycle);27: a C₃₋₁₀ cycloalkylthio group (wherein the cycloalkyl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);28: a C₆₋₁₀ arylthio group (wherein the aryl is optionally substitutedwith one to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);29: a 5- to 12-membered monocyclic or polycyclic heterocyclylthio group(wherein the heterocycle is optionally substituted with one to threegroups selected from the group consisting of a halogen atom, hydroxy,C₁₋₆ alkyl, and C₁₋₆ alkoxy);30: a sulfinate group;31: a C₁₋₆ alkylsulfinyl group (wherein the alkyl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, amino (which is optionally substituted withone or two C₁₋₆ alkyl), C₁₋₆ alkoxy, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, and a5- to 12-membered monocyclic or polycyclic heterocycle);32: a C₃₋₁₀ cycloalkylsulfinyl group (wherein the cycloalkyl isoptionally substituted with one to three groups selected from the groupconsisting of a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);33: a C₆₋₁₀ arylsulfinyl group (wherein the aryl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);34: a 5- to 12-membered monocyclic or polycyclic heterocyclylsulfinylgroup (wherein the heterocycle is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);35: an aminosulfinyl group (wherein the amino is optionally substitutedwith one or two groups selected from the group consisting of(a) C₁₋₆ alkyl (wherein the alkyl is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₄ alkoxy, C₆₋₁₀ aryl, and a 5- to 12-membered monocyclic orpolycyclic heterocycle (which is optionally substituted with one tothree C₁₋₆ alkyl)),(b) C₃₋₁₀ cycloalkyl (wherein the cycloalkyl is optionally substitutedwith one to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy),(c) C₆₋₁₀ aryl (wherein the aryl is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy), and(d) a 5- to 12-membered monocyclic or polycyclic heterocycle (whereinthe heterocycle is optionally substituted with one to three groupsselected from the group consisting of a halogen atom, hydroxy, C₁₋₆alkyl, and C₁₋₆ alkoxy));36: a 3- to 8-membered cyclic aminosulfinyl group (wherein the cyclicamino is optionally substituted with one to three C₁₋₆ alkyl);37: a sulfonate group;38: a C₁₋₆ alkylsulfonyl group (wherein the alkyl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, amino (which is optionally substituted withone or two C₁₋₆ alkyl), C₁₋₆ alkoxy, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, and a5- to 12-membered monocyclic or polycyclic heterocycle);39: a C₃₋₁₀ cycloalkylsulfonyl group (wherein the cycloalkyl isoptionally substituted with one to three groups selected from the groupconsisting of a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);40: a C₆₋₁₀ arylsulfonyl group (wherein the aryl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);41: a 5- to 12-membered monocyclic or polycyclic heterocyclylsulfonylgroup (wherein the heterocycle is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);42: an aminosulfonyl group (wherein the amino is optionally substitutedwith one or two groups selected from the group consisting of(a) C₁₋₆ alkyl (wherein the alkyl is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₄ alkoxy, C₆₋₁₀ aryl, and a 5- to 12-membered monocyclic orpolycyclic heterocycle (which is optionally substituted with one tothree C₁₋₆ alkyl)),(b) C₃₋₁₀ cycloalkyl (wherein the cycloalkyl is optionally substitutedwith one to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy),(c) C₆₋₁₀ aryl (wherein the aryl is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy), and(d) a 5- to 12-membered monocyclic or polycyclic heterocycle (whereinthe heterocycle is optionally substituted with one to three groupsselected from the group consisting of a halogen atom, hydroxy, C₁₋₆alkyl, and C₁₋₆ alkoxy)); and43: a 3- to 8-membered cyclic aminosulfonyl group (wherein the cyclicamino is optionally substituted with one to three C₁₋₆ alkyl).Item 16: The compound according to item 15 or a pharmacologicallyacceptable salt thereof, wherein R³, R⁴, or R⁵ is each independently agroup selected from the group consisting of:1: a hydrogen atom;2: a halogen atom;3: a cyano group;4: a hydroxyl group;5: an amino group (wherein the amino is optionally substituted with oneor two groups selected from the group consisting of(a) C₁₋₆ alkyl (wherein the alkyl is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₄ alkoxy, C₆₋₁₀ aryl, and a 5- to 12-membered monocyclic orpolycyclic heterocycle (which is optionally substituted with one tothree C₁₋₆ alkyl)),(b) C₁₋₆ alkylcarbonyl (wherein the alkyl is optionally substituted withone to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₄ alkoxy, C₆₋₁₀ aryl, and a 5- to 12-memberedmonocyclic or polycyclic heterocycle (which is optionally substitutedwith one to three C₁₋₆ alkyl)),(c) C₃₋₁₀ cycloalkyl (wherein the cycloalkyl is optionally substitutedwith one to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy),(d) C₆₋₁₀ aryl (wherein the aryl is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy), and(e) a 5- to 12-membered monocyclic or polycyclic heterocycle (whereinthe heterocycle is optionally substituted with one to three groupsselected from the group consisting of a halogen atom, hydroxy, C₁₋₆alkyl, and C₁₋₆ alkoxy));6: a 3- to 8-membered cyclic amino group (wherein the cyclic amino isoptionally substituted with one to three C₁₋₆ alkyl);7: a C₁₋₆ alkyl group (wherein the alkyl is optionally substituted withone to three groups selected from the group consisting of a halogenatom, hydroxy, amino (which is optionally substituted with one or twoC₁₋₆ alkyl groups), C₁₋₆ alkoxy, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, and a 5-to 12-membered monocyclic or polycyclic heterocycle);8: a C₁₋₆ alkoxy group (wherein the alkyl is optionally substituted withone to three groups selected from the group consisting of a halogenatom, hydroxy, amino (which is optionally substituted with one or twoC₁₋₆ alkyl groups), C₁₋₆ alkoxy, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, and a 5-to 12-membered monocyclic or polycyclic heterocycle);9: a C₁₋₆ alkylcarbonyl group (wherein the alkyl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, amino (which is optionally substituted withone or two C₁₋₆ alkyl groups), C₁₋₆ alkoxy, C₃₋₁₀ cycloalkyl, C₆₋₁₀aryl, and a 5- to 12-membered monocyclic or polycyclic heterocycle);10: an aminocarbonyl group (wherein the amino is optionally substitutedwith one or two groups selected from the group consisting of(a) C₁₋₆ alkyl (wherein the alkyl is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₄ alkoxy, C₆₋₁₀ aryl, and a 5- to 12-membered monocyclic orpolycyclic heterocycle (which is optionally substituted with one tothree C₁₋₆ alkyl)),(b) C₃₋₁₀ cycloalkyl (wherein the cycloalkyl is optionally substitutedwith one to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy),(c) C₆₋₁₀ aryl (wherein the aryl is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy), and(d) a 5- to 12-membered monocyclic or polycyclic heterocycle (whereinthe heterocycle is optionally substituted with one to three groupsselected from the group consisting of a halogen atom, hydroxy, C₁₋₆alkyl, and C₁₋₆ alkoxy));11: a 3- to 8-membered cyclic aminocarbonyl group (wherein the cyclicamino is optionally substituted with one to three C₁₋₆ alkyl);12: a C₁₋₆ alkylsulfonyl group (wherein the alkyl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, amino (which is optionally substituted withone or two C₁₋₆ alkyl), C₁₋₆ alkoxy, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, and a5- to 12-membered monocyclic or polycyclic heterocycle);13: an aminosulfonyl group (wherein the amino is optionally substitutedwith one or two groups selected from the group consisting of(a) C₁₋₆ alkyl (wherein the alkyl is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₄ alkoxy, C₆₋₁₀ aryl, and a 5- to 12-membered monocyclic orpolycyclic heterocycle (which is optionally substituted with one tothree C₁₋₆ alkyl)),(b) C₃₋₁₀ cycloalkyl (wherein the cycloalkyl is optionally substitutedwith one to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy),(c) C₆₋₁₀ aryl (wherein the aryl is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy), and(d) a 5- to 12-membered monocyclic or polycyclic heterocycle (whereinthe heterocycle is optionally substituted with one to three groupsselected from the group consisting of a halogen atom, hydroxy, C₁₋₆alkyl, and C₁₋₆ alkoxy)); and14: a 3- to 8-membered cyclic aminosulfonyl group (wherein the cyclicamino is optionally substituted with one to three C₁₋₆ alkyl).Item 17: The compound according to item 16 or a pharmacologicallyacceptable salt thereof, wherein R³, R⁴, or R⁵ is all hydrogen atoms.Item 18: The compound according to any one of item 1 or 4-17 or apharmacologically acceptable salt thereof, wherein R⁶ is a groupselected from the group consisting of:1: a hydrogen atom;2: a C₁₋₆ alkyl group (wherein the alkyl is optionally substituted withone to three groups selected from the group consisting of a halogenatom, C₁₋₆ alkoxy, C₆₋₁₀ aryl, and a 5- to 6-membered monocyclicheterocycle (which is optionally substituted with one to three C₁₋₄alkyl));3: a C₃₋₁₀ cycloalkyl group (wherein the cycloalkyl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);4: a C₁₋₆ alkylcarbonyl group (wherein the alkyl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, C₁₋₆ alkoxy, C₆₋₁₀ aryl, and a 5- to 6-memberedmonocyclic heterocycle (which is optionally substituted with one tothree C₁₋₄ alkyl));5: a C₃₋₁₀ cycloalkylcarbonyl group;6: a C₆₋₁₀ arylcarbonyl group;7: a 5- to 12-membered monocyclic or polycyclic heterocyclylcarbonylgroup;8: a C₁₋₆ alkoxycarbonyl group (wherein the alkyl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, C₁₋₆ alkoxy, C₆₋₁₀ aryl, and a 5- to 6-memberedmonocyclic heterocycle (which is optionally substituted with one tothree C₁₋₄ alkyl));9: a C₃₋₁₀ cycloalkyloxycarbonyl group (wherein the cycloalkyl isoptionally substituted with one to three groups selected from the groupconsisting of a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);10: a C₆₋₁₀ aryloxycarbonyl group (wherein the aryl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);11: a 5- to 12-membered monocyclic or polycyclic heterocyclyloxycarbonylgroup (wherein the heterocycle is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);12: a C₁₋₆ alkylsulfinyl group (wherein the alkyl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, C₁₋₆ alkoxy, C₆₋₁₀ aryl, and a 5- to 6-memberedmonocyclic heterocycle (which is optionally substituted with one tothree C₁₋₄ alkyl));13: a C₃₋₁₀ cycloalkylsulfinyl group (wherein the cycloalkyl isoptionally substituted with one to three groups selected from the groupconsisting of a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);14: a C₆₋₁₀ arylsulfinyl group (wherein the aryl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);15: a 5- to 12-membered monocyclic or polycyclic heterocyclylsulfinylgroup (wherein the heterocycle is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);16: a C₁₋₆ alkylsulfonyl group (wherein the alkyl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, C₁₋₆ alkoxy, C₆₋₁₀ aryl, and a 5- to 6-memberedmonocyclic heterocycle (which is optionally substituted with one tothree C₁₋₄ alkyl));17: a C₃₋₁₀ cycloalkylsulfonyl group (wherein the cycloalkyl isoptionally substituted with one to three groups selected from the groupconsisting of a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);18: a C₆₋₁₀ arylsulfonyl group (wherein the aryl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);19: a 5- to 12-membered monocyclic or polycyclic heterocyclylsulfonylgroup (wherein the heterocycle is optionally substituted with one tothree groups selected from the group consisting of a halogen atom,hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy);20: a C₆₋₁₀ aryl group (wherein the aryl is optionally substituted withone to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy); and21: a 5- to 12-membered monocyclic or polycyclic heterocyclic group(wherein the heterocycle is optionally substituted with one to threegroups selected from the group consisting of a halogen atom, hydroxy,C₁₋₆ alkyl, and C₁₋₆ alkoxy).Item 19: The compound according to item 18 or a pharmacologicallyacceptable salt thereof, wherein R⁶ is a group selected from the groupconsisting of:1: a hydrogen atom;2: a C₁₋₆ alkyl group (wherein the alkyl is optionally substituted withone to three groups selected from the group consisting of a halogenatom, C₁₋₆ alkoxy, C₆₋₁₀ aryl, and a 5- to 6-membered monocyclicheterocycle (which is optionally substituted with one to three C₁₋₄alkyl));3: a C₁₋₆ alkylcarbonyl group (wherein the alkyl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, C₁₋₆ alkoxy, C₆₋₁₀ aryl, and a 5- to 6-memberedmonocyclic heterocycle (which is optionally substituted with one tothree C₁₋₄ alkyl)); and4: a C₁₋₆ alkylsulfonyl group (wherein the alkyl is optionallysubstituted with one to three groups selected from the group consistingof a halogen atom, C₁₋₆ alkoxy, C₆₋₁₀ aryl, and a 5- to 6-memberedmonocyclic heterocycle (which is optionally substituted with one tothree C₁₋₄ alkyl)).Item 20: The compound according to item 19 or a pharmacologicallyacceptable salt thereof, wherein R⁶ is a hydrogen atom.Item 21: The compound according to items 1-20 or a pharmacologicallyacceptable salt thereof, wherein R² is a group selected from the groupconsisting of:1: a C₁₋₆ alkyl group (wherein the alkyl is optionally substituted withone to three groups selected from the group consisting of a halogenatom, hydroxy, amino (which is optionally substituted with one or twoC₁₋₆ alkyl groups), C₁₋₄ alkoxy, C₃₋₈ cycloalkyl, and a 5- to 6-memberedmonocyclic heterocycle);2: a C₁₋₆ alkylcarbonyl group;3: an aminocarbonyl group (wherein the amino is optionally substitutedwith one to three C₁₋₆ alkyl groups (wherein the alkyl is optionallysubstituted with one to three halogen atoms)); and4: a 3- to 8-membered cyclic aminocarbonyl group (wherein the cyclicamino is optionally substituted with one to three C₁₋₆ alkyl).Item 22: The compound according to item 1 or a pharmacologicallyacceptable salt thereof, wherein

A is O or S;

the ring G is either one selected from the group consisting of thefollowing formula (b) or (e):

R¹ is a hydrogen atom; andR² is a group selected from the group consisting of:1: a C₁₋₆ alkyl group (wherein the alkyl is optionally substituted withone to three groups selected from the group consisting of a halogenatom, hydroxy, amino (which is optionally substituted with one or twoC₁₋₆ alkyl groups), C₁₋₄ alkoxy, C₃₋₈ cycloalkyl, and a 5- to 6-memberedmonocyclic heterocycle);2: a C₁₋₆ alkylcarbonyl group;3: an aminocarbonyl group (wherein the amino is optionally substitutedwith one to three C₁₋₆ alkyl groups (wherein the alkyl is optionallysubstituted with one to three halogen atoms)); and4: a 3- to 8-membered cyclic aminocarbonyl group (wherein the cyclicamino is optionally substituted with one to three C₁₋₆ alkyl).R³, R⁴, and R⁵ are hydrogen atoms.Item 23: The compound according to item 1 or a pharmaceuticallyacceptable salt thereof, wherein the compound is selected from thefollowing compounds:

-   2-acetylthieno[2,3-g]quinoline-4,9-dione;-   2-acetylthieno[2,3-g]isoquinoline-4,9-dione;-   2-(1-hydroxyethyl)thieno[2,3-g]isoquinoline-4,9-dione;-   2-(2-hydroxypropan-2-yl)thieno[2,3-g]isoquinoline-4,9-dione;-   2-[cyclopropyl(hydroxy)methyl]thieno[2,3-g]isoquinoline-4,9-dione;-   N,N-dimethyl-4,9-dioxo-4,9-dihydrothieno[2,3-g]isoquinoline-2-carboxyamide;-   2-(morpholin-4-ylcarbonyl)thieno[2,3-g]isoquinoline-4,9-dione;-   N-(2,2-difluoroethyl)-4,9-dioxo-4,9-dihydrothieno[2,3-g]isoquinoline-2-carboxyamide;-   2-{[ethyl(2-methoxyethyl)amino]methyl}thieno[2,3-g]isoquinoline-4,9-dione;-   2-{[(2,2-difluoroethyl)amino]methyl}thieno[2,3-g]isoquinoline-4,9-dione;-   2-[(4-acetylpiperazin-1-yl)methyl]thieno[2,3-g]isoquinoline-4,9-dione;-   4,9-dioxo-4,9-dihydrothieno[2,3-g]isoquinoline-2-carbonitrile;-   2-(1-fluoroethyl)thieno[2,3-g]isoquinoline-4,9-dione;-   2-(3-ethyl-1,2,4-oxadiazol-5-yl)thieno[2,3-g]isoquinoline-4,9-dione;-   2-acetylthieno[3,2-g]isoquinoline-4,9-dione;-   N-(2,2-difluoroethyl)-4,9-dioxo-4,9-dihydrofuro[2,3-g]isoquinoline-2-carboxamide;-   2-(1-hydroxyethyl)furo[3,2-g]isoquinoline-4,9-dione;-   2-acetylthieno[3,2-f][1]benzofuran-4,8-dione; and-   2-(morpholin-4-ylcarbonyl)thieno[3,2-f][1]benzofuran-4,8-dione.    Item 24: A pharmaceutical composition comprising a compound    according to any one of items 1-23 or a pharmacologically acceptable    salt thereof.    Item 25: An anticancer agent comprising a compound according to any    one of items 1-23 or a pharmacologically acceptable salt thereof as    an active ingredient.    Item 26: The anticancer agent according to item 25, wherein the    cancer is at least one cancer selected from the group consisting of    acute leukemia, chronic lymphocytic leukemia, chronic myelocytic    leukemia, polycythemia vera, malignant lymphoma, brain tumor, head    and neck cancer, esophageal cancer, thyroid cancer, small cell lung    cancer, non-small-cell lung cancer, breast cancer, gastric cancer,    gallbladder•bile duct cancer, hepatoma, pancreatic cancer, colon    cancer, rectal cancer, chorioepithelioma, endometrial cancer,    cervical cancer, urothelial cancer, renal cell cancer, testicular    tumor, Wilms' tumor, skin cancer, malignant melanoma, neuroblastoma,    osteosarcoma, Ewing's sarcoma, and soft tissue sarcoma.    Item 27: A method for treating a cancer, characterized by    administering a therapeutically effective amount of a compound    according to any one of items 1-23 or a pharmacologically acceptable    salt thereof to a patient in need of the treatment.    Item 28: The method for treating according to item 27, wherein the    cancer is at least one cancer selected from the group consisting of    acute leukemia, chronic lymphocytic leukemia, chronic myelocytic    leukemia, polycythemia vera, malignant lymphoma, brain tumor, head    and neck cancer, esophageal cancer, thyroid cancer, small cell lung    cancer, non-small-cell lung cancer, breast cancer, gastric cancer,    gallbladder•bile duct cancer, hepatoma, pancreatic cancer, colon    cancer, rectal cancer, chorioepithelioma, endometrial cancer,    cervical cancer, urothelial cancer, renal cell cancer, testicular    tumor, Wilms' tumor, skin cancer, malignant melanoma, neuroblastoma,    osteosarcoma, Ewing's sarcoma, and soft tissue sarcoma.    Item 29: The use of a compound according to any one of items 1-23 or    a pharmacologically acceptable salt thereof for the manufacture of a    therapeutic agent for cancer.    Item 30: The use of a compound according to item 29 or a    pharmacologically acceptable salt thereof, wherein the cancer is at    least one cancer selected from the group consisting of acute    leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia,    polycythemia vera, malignant lymphoma, brain tumor, head and neck    cancer, esophageal cancer, thyroid cancer, small cell lung cancer,    non-small-cell lung cancer, breast cancer, gastric cancer,    gallbladder•bile duct cancer, hepatoma, pancreatic cancer, colon    cancer, rectal cancer, chorioepithelioma, endometrial cancer,    cervical cancer, urothelial cancer, renal cell cancer, testicular    tumor, Wilms' tumor, skin cancer, malignant melanoma, neuroblastoma,    osteosarcoma, Ewing's sarcoma, and soft tissue sarcoma.    Item 31: A compound according to any one of items 1-23 or a    pharmacologically acceptable salt thereof for use in treating    cancer.    Item 32: The compound according to item 31 or a pharmacologically    acceptable salt thereof, wherein the cancer is at least one cancer    selected from the group consisting of acute leukemia, chronic    lymphocytic leukemia, chronic myelocytic leukemia, polycythemia    vera, malignant lymphoma, brain tumor, head and neck cancer,    esophageal cancer, thyroid cancer, small cell lung cancer,    non-small-cell lung cancer, breast cancer, gastric cancer,    gallbladder•bile duct cancer, hepatoma, pancreatic cancer, colon    cancer, rectal cancer, chorioepithelioma, endometrial cancer,    cervical cancer, urothelial cancer, renal cell cancer, testicular    tumor, Wilms' tumor, skin cancer, malignant melanoma, neuroblastoma,    osteosarcoma, Ewing's sarcoma, and soft tissue sarcoma.    Item 33: A method of producing a compound represented by formula (1)    or a pharmacologically acceptable salt thereof:

wherein A, R¹, R², R³, R⁴, and R⁵ are defined as in above item 1,wherein the method is characterized by comprising a step of mixing acompound represented by formula (2) or a salt thereof:

wherein A, R¹, R², R³, R⁴, and R⁵ are defined as in above item 1; R⁷ andR⁸ are each C₁₋₆ alkyl (wherein the alkyl is optionally substituted withone to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₄ alkoxy, C₆₋₁₀ aryl, and a 5- to 12-memberedmonocyclic or polycyclic heterocycle (which is optionally substitutedwith one to three C₁₋₆ alkyl)), with an oxidant.Item 34: A method of producing a compound represented by formula (1) ora pharmacologically acceptable salt thereof:

wherein A, R¹, R², R³, R⁴, and R⁵ are defined as in above item 1, andwherein the method is characterized by comprising a step of mixing acompound represented by formula (2) or a salt thereof:

wherein A, R¹, R², R³, R⁴, and R⁵ are defined as in above item 1, or R¹and R² are optionally substituted alkoxycarbonyl groups, and R⁷ and R⁸are each C₁₋₆ alkyl (wherein the alkyl is optionally substituted withone to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₄ alkoxy, C₆₋₁₀ aryl, and a 5- to 12-memberedmonocyclic or polycyclic heterocycle (which is optionally substitutedwith one to three C₁₋₆ alkyl)), with an oxidant.Item 35: A compound represented by the following formula (2) or a saltthereof:

wherein A, R¹, R², R³, R⁴, and R⁵ are defined as in above item 1, and R⁷and R⁸ are each C₁₋₆ alkyl (wherein the alkyl is optionally substitutedwith one to three groups selected from the group consisting of a halogenatom, hydroxy, C₁₋₄ alkoxy, C₆₋₁₀ aryl, and a 5- to 12-memberedmonocyclic or polycyclic heterocycle (which is optionally substitutedwith one to three C₁₋₆ alkyl)).

Moreover, it will be understood that the characteristics of theabove-described embodiments of the present invention can be used aloneor in combination. Accordingly, in the present invention, it is intendedthat in addition to the clarified combinations, the above-mentioned oneor more characteristics can be further combined and provided.

Advantageous Effects of Invention

The compounds represented by the formula (1) or the pharmacologicallyacceptable salts thereof (also referred to as the present compound(s))exhibit strong inhibitory effects on proliferation of a cancer cell andcancer cell sphere-forming ability, and these compounds are useful, forexample, as medicament to be effective in prevention and/or treatment ofcancer.

DESCRIPTION OF EMBODIMENTS

The present invention is described below in more detail.

In the present specification, the number of substituents of a groupdefined by “an optionally substituted” or “substituted” is notparticularly limited if it is substitutable, and is one or plural. Inaddition, unless otherwise indicated, the description for each group isalso applied when the group is one part of or a substituent on othergroups.

In the present specification, examples of “halogen atom” include afluorine atom, a chlorine atom, a bromine atom, and an iodine atom.Preferably, it is a fluorine atom or a chlorine atom.

A “C₁₋₆ alkyl group” means a linear or branched, saturated hydrocarbongroup of which the carbon number is one to six. Preferably, it includesa “C₁₋₄ alkyl group” and the like. Specific examples of the “C₁₋₆ alkylgroup” include, for example, methyl, ethyl, propyl, 1-methylethyl,butyl, 2-methylpropyl, 1-methylpropyl, 1,1-dimethylethyl, pentyl,3-methylbutyl, 2-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl,1,1-dimethylpropyl, hexyl, 4-methylpentyl, 3-methylpentyl,2-methylpentyl, 1-methylpentyl, and the like. Specific examples of the“C₁₋₄ alkyl group” include those having a carbon number from 1 to 4 thatare exemplified in the specific examples of “C₁₋₁₀ alkyl group”. In thespecification, for example, C₁₋₆ represents that the carbon number isone to six, C₁₋₄ represents that the carbon number is one to four, or C₆represents that the carbon number is six. The same applies to cases ofother numbers.

A “C₂₋₆ alkenyl group” means a linear or branched, unsaturatedhydrocarbon group that has two to six carbons and contains one to threedouble bonds. Specific examples of “C₂₋₆ alkenyl group” include, forexample, vinyl, propenyl, methylpropenyl, butenyl, methylbutenyl,pentenyl, hexenyl, and the like.

A “C₂₋₆ alkynyl group” means a linear or branched, unsaturatedhydrocarbon group that has two to six carbons and contains one triplebond. Specific examples of “C₂₋₆ alkynyl group” include, for example,propynyl, methylpropynyl, butynyl, methylbutynyl, pentynyl, hexynyl, andthe like.

A “C₃₋₁₀ cycloalkyl group” means a cyclic saturated hydrocarbon group ofwhich the carbon number is three to ten, and also includes those havinga partially crosslinked structure. Preferably, it includes a “C₃₋₇cycloalkyl group” and the like. Specific examples of “C₃₋₁₀ cycloalkylgroup” include, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl,and the like. Specific examples of “C₃₋₇ cycloalkyl group” include, forexample, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,and the like. The “C₃₋₁₀ cycloalkyl group” also encompasses a compoundfused to an aromatic ring. Specific examples thereof include, forexample, groups represented by the following:

and the like.

A “C₁₋₆ alkoxy group” refers to a “C₁₋₆ alkyloxy group” and the “C₁₋₆alkyl” moiety in a “C₁₋₆ alkoxy group” is defined the same as theabove-described “C₁₋₆ alkyl”. The “C₁₋₆ alkoxy group” includes,preferably, a “C₁₋₄ alkoxy group” and the like. Examples of “C₁₋₆ alkoxygroup” include, for example, methoxy, ethoxy, propoxy, 1-methylethoxy,butoxy, 2-methylpropoxy, 1-methylpropoxy, 1,1-dimethylethoxy, pentyloxy,3-methylbutoxy, 2-methylbutoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy,1,1-dimethylpropoxy, hexyloxy, 4-methylpentyloxy, 3-methylpentyloxy,2-methylpentyloxy, 1-methylpentyloxy, 3,3-dimethylbutoxy,2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, and thelike.

The “C₃₋₁₀ cycloalkyl” moiety in a “C₃₋₁₀ cycloalkyloxy group” isdefined the same as the above described “C₃₋₁₀ cycloalkyl group”.Preferably, it is a “C₃₋₇ cycloalkyloxy group” and the like. Examples of“C₃₋₁₀ cycloalkyloxy group” include, for example, cyclopropoxy,cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and thelike.

The “C₁₋₆ alkyl” moiety in a “C₁₋₆ alkylcarbonyl group” is defined thesame as the above-described “C₁₋₆ alkyl group”. The “C₁₋₆ alkylcarbonylgroup” includes, preferably, a “C₁₋₄ alkylcarbonyl group” and the like.Specific examples of “C₁₋₆ alkylcarbonyl group” include, for example,methylcarbonyl, ethylcarbonyl, propylcarbonyl, 1-methylethylcarbonyl,butylcarbonyl, 2-methylpropylcarbonyl, 1-methylpropylcarbonyl,1,1-dimethylethylcarbonyl, and the like.

The “C₃₋₁₀ cycloalkyl” moiety in a “C₃₋₁₀ cycloalkylcarbonyl group” isdefined the same as the above described “C₃₋₁₀ cycloalkyl group”.Preferably, it is a “C₃₋₇ cycloalkylcarbonyl group” and the like.Specific examples of “C₃₋₁₀ cycloalkylcarbonyl group” include, forexample, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl,cyclohexylcarbonyl, cycloheptylcarbonyl, and the like.

The “C₁₋₆ alkylcarbonyl” moiety in a “C₁₋₆ alkylcarbonyloxy group” isdefined the same as the above-described “C₁₋₆ alkylcarbonyl group”. The“C₁₋₆ alkylcarbonyloxy group” includes, preferably, a “C₁₋₄alkylcarbonyloxy group” and the like. Specific examples of “C₁₋₆alkylcarbonyloxy group” include methylcarbonyloxy, ethylcarbonyloxy,propylcarbonyloxy, 1-methylethylcarbonyloxy, butylcarbonyloxy,2-methylpropylcarbonyloxy, 1-methylpropylcarbonyloxy,1,1-dimethylethylcarbonyloxy, and the like.

The “C₁₋₆ alkylcarbonyl” moiety in a “C₁₋₆ alkylcarbonylamino group” isdefined the same as the above-described “C₁₋₆ alkylcarbonyl group”.Specific examples of “C₁₋₆ alkylcarbonylamino group” include, forexample, methylcarbonylamino, ethylcarbonylamino, and the like.

The “C₁₋₆ alkyl” moiety in a “C₁₋₆ alkylthio group” is defined the sameas the above-described “C₁₋₆ alkyl group”. The “C₁₋₆ alkylthio group”includes, preferably, “C₁₋₄ alkylthio group” and the like. Specificexamples of “C₁₋₆ alkylthio group” include, for example, methylthio,ethylthio, propylthio, 1-methylethylthio, butylthio, 2-methylpropylthio,1-methylpropylthio, 1,1-dimethylethylthio, and the like.

The “C₃₋₁₀ cycloalkyl” moiety in a “C₃₋₁₀ cycloalkylthio group” isdefined the same as the above-described “C₃₋₁₀ cycloalkyl group”.Preferably, it is a “C₃₋₇ cycloalkylthio group” and the like. Specificexamples of “C₃₋₁₀ cycloalkylthio group” include, for example,cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio,cycloheptylthio, and the like.

The “C₁₋₆ alkyl” moiety in a “C₁₋₆ alkylsulfinyl group” is defined thesame as the above-described “C₁₋₆ alkyl group”. The “C₁₋₆ alkylsulfinylgroup” includes, preferably, “C₁₋₄ alkylsulfinyl group” and the like.Specific examples of “C₁₋₆ alkylsulfinyl group” include, for example,methylsulfinyl, ethylsulfinyl, propylsulfinyl, 1-methylethylsulfinyl,butylsulfinyl, 2-methylpropylsulfinyl, 1-methylpropylsulfinyl,1,1-dimethylethylsulfinyl, and the like.

The “C₃₋₁₀ cycloalkyl” moiety in a “C₃₋₁₀ cycloalkylsulfinyl group” isdefined the same as the above-described “C₃₋₁₀ cycloalkyl group”.Preferably, it is a “C₃₋₇ cycloalkylsulfinyl group” and the like.Specific examples of “C₃₋₁₀ cycloalkylsulfinyl group” include, forexample, cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentylsulfinyl,cyclohexylsulfinyl, cycloheptylsulfinyl, and the like.

The “C₁₋₆ alkyl” moiety in a “C₁₋₆ alkylsulfonyl group” is defined thesame as the above-described “C₁₋₆ alkyl group”. Preferably, it includesa “C₁₋₄ alkylsulfonyl group” and the like. Specific examples of “C₁₋₆alkylsulfonyl group” include, for example, methylsulfonyl,ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl,pentylsulfonyl, hexylsulfonyl, and the like.

The “C₃₋₁₀ cycloalkyl” moiety in a “C₃₋₁₀ cycloalkylsulfonyl group” isdefined the same as the above-described “C₃₋₁₀ cycloalkyl group”.Preferably, it is a “C₃₋₇ cycloalkylsulfonyl group” and the like.Specific examples of “C₃₋₁₀ cycloalkylsulfonyl group” include, forexample, cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl,cyclohexylsulfonyl, cycloheptylsulfonyl, and the like.

The “C₁₋₆ alkoxy” moiety in a “C₁₋₆ alkoxycarbonyl group” is defined thesame as the above-described “C₁₋₆ alkoxy group”. Specific examples of“C₁₋₆ alkoxycarbonyl group” include, for example, methoxycarbonyl,ethoxycarbonyl, and the like. In the relevant field, although an“alkoxycarbonyl group” may be referred to as an “alkyloxycarbonylgroup”, the two are synonymous.

The “C₃₋₁₀ cycloalkyl” moiety in a “C₃₋₁₀ cycloalkyloxycarbonyl group”is defined the same as the above-described “C₃₋₁₀ cycloalkyl group”.Preferably, it is a “C₃₋₇ cycloalkyloxycarbonyl group” and the like.Specific examples of “C₃₋₁₀ cycloalkyloxycarbonyl group” include, forexample, cyclopropyloxycarbonyl, cyclobutyloxycarbonyl,cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, cycloheptyloxycarbonyl,and the like.

A “C₆₋₁₀ aryl group” means an aromatic hydrocarbon of which the carbonnumber is six to ten. Specific examples of “C₆₋₁₀ aryl group” include,for example, phenyl, 1-naphthyl, 2-naphthyl, and the like. Particularlypreferably, it includes a phenyl group. The “C₆₋₁₀ aryl group” alsoencompasses a 8- to 14-membered polycyclic group in which an aromaticring and a C₄₋₆ cycloalkyl are ring-fused, or 9- to 14-memberedpolycyclic group in which an aromatic ring is fused to, for example, 5-to 6-membered heterocyclic group having one to three atoms that areidentical or different and are selected from a nitrogen atom, an oxygenatom, or a sulfur atom. Specific examples thereof include, for example,groups represented by the following:

and the like.

Examples of “heterocyclic group” include 3- to 10-membered heterocyclicgroup having one to three atoms that are identical or different and areselected from a nitrogen atom, an oxygen atom, or a sulfur atom, and thelike. Preferably, it is a 4- to 7-membered group, more preferably, a 5-or 6-membered group. All the aforementioned nitrogen atom, oxygen atom,and sulfur atom are atoms constituting a ring. The heterocyclic groupmay be any of saturated, partially unsaturated, or unsaturatedheterocyclic groups, and a saturated heterocyclic group is morepreferred. Specific examples of “heterocyclic group” include epoxy,aziridine, azetidine, pyranyl, tetrahydrofuryl, pyrrolidinyl,imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,dioxothiomorpholinyl, hexamethyleneiminyl, oxazolidinyl, thiazolidinyl,imidazolidinyl, oxoimidazolidinyl, dioxoimidazolidinyl, oxooxazolidinyl,dioxooxazolidinyl, dioxothiazolidinyl, tetrahydrofuranyl,tetrahydropyridinyl, oxetanyl, tetrahydropyranyl, and the like. It isnoted that the group encompasses heterocyclic groups having a bridgestructure. In the group, a bond on the “group” cannot be from a nitrogenatom constituting a ring. That is, the group does not encompass theconcept of, for example, a 1-pyrrolidino group and the like.

The aforementioned “heterocyclic group” may form a fused ring with a6-membered aromatic hydrocarbon or a 6-membered heteroaryl. Examplesthereof include a bicyclic “heterocycle” having eleven or twelvering-constituting atoms, wherein the foregoing 5- or 6-membered“heterocyclic ring” is fused to a 6-membered aromatic hydrocarbon or a6-membered heteroaryl. Examples of the 6-membered aromatic hydrocarboninclude benzene and the like. Examples of a 6-membered unsaturatedheterocyclic group include pyridine, pyrimidine, pyridazine, and thelike. Specific examples of the fused ring include dihydroindolyl,dihydroisoindolyl, dihydropurinyl, dihydrothiazolopyrimidinyl,dihydrobenzodioxanyl, isoindolyl, indazolyl, pyrrolidinyl,tetrahydroquinolinyl, decahydroquinolinyl, tetrahydroisoquinolinyl,decahydroisoquinolinyl, tetrahydronaphthyridinyl,tetrahydropyridoazepinyl, and the like.

Examples of a “saturated heterocyclic group” include a 5- to 10-memberedmonocyclic or polycyclic group and the like. The group contains one ormore (e.g., one to four) heteroatoms that are identical or different andare selected from a nitrogen atom, a sulfur atom, or an oxygen atom.Preferably, examples thereof include a 5- or 6-membered monocyclicheteroaryl group, and the like. Specific examples of a “heteroarylgroup” include, for example, pyrrolyl, thienyl, benzothienyl,benzofuranyl, benzoxazolyl, benzothiazolyl, furyl, oxazolyl, triazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, benzisoxazolyl, benzisothiazolyl,imidazolyl, pyrazolyl, pyridyl, pyrazyl, pyrimidyl, pyridazyl, quinolyl,isoquinolyl, triazolyl, triazinyl, tetrazolyl, indolyl,imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl,[1,2,4]triazolo[1,5-a]pyridyl, benzimidazolyl, quinoxalyl, cinnolyl,quinazolyl, indazolyl, naphthyridyl, quinolinolyl, isoquinolinolyl, andthe like.

The “heterocycle” moiety in a “heterocyclyloxy group” is defined thesame as the above-described “heterocyclic group”. It is preferably 4- to7-membered, and more preferably 5- or 6-membered. Specific examplesthereof include a 4-pyranyloxy group and the like.

The “heterocycle” moiety in a “heterocyclylthio group” is defined thesame as the above-described “heterocyclic group”. It is preferably 4- to7-membered, and more preferably 5- or 6-membered. Specific examplesthereof include a 4-pyranylthio group and the like.

The “heterocycle” moiety in a “heterocyclyloxycarbonyl group” is definedthe same as the above-described “heterocyclic group”. It is preferably4- to 7-membered, and more preferably 5- or 6-membered. Specificexamples thereof include a pyranyloxycarbonyl group and the like.

The “heterocycle” moiety in a “heterocyclylsulfinyl group” is definedthe same as the above-described “heterocyclic group”.

It is preferably 4- to 7-membered, and more preferably 5- or 6-membered.Specific examples thereof include a pyranylsulfinyl group and the like.

The “heterocycle” moiety in a “heterocyclylsulfonyl group” is definedthe same as the above-described “heterocyclic group”. It is preferably4- to 7-membered, and more preferably 5- or 6-membered. Specificexamples thereof include a pyranylsulfonyl group and the like.

The “C₆₋₁₀ aryl” moiety in a “C₆₋₁₀ aryloxy group” is defined the sameas the above-described “C₆₋₁₀ aryl group”. It preferably includes a “C₆aryloxy group” (phenoxy group). Specific groups thereof include, forexample, phenoxy, 1-naphthoxy, 2-naphthoxy, and the like.

The “C₆₋₁₀ aryl” moiety in a “C₆₋₁₀ arylthio group” is defined the sameas the above-described “C₆₋₁₀ aryl group”. It includes preferably a “C₆arylthio group”. Specific examples thereof include, for example,phenylthio, 1-naphthylthio, 2-naphthylthio, and the like.

A “C₆₋₁₀ arylcarbonyl group” means a group having the above-described“C₆₋₁₀ aryl group” bound with a carbonyl group. The “C₆₋₁₀ aryl” moietyis defined the same as the above-described “C₆₋₁₀ aryl group”. Itpreferably includes a “C₆ arylcarbonyl group” (a phenylcarbonyl group).Specific examples of the “C₆₋₁₀ arylcarbonyl group” include, forexample, benzoyl, 1-naphthoyl, 2-naphthoyl, and the like.

The “C₆₋₁₀ aryl” moiety in a “C₆₋₁₀ arylsulfinyl group” is defined thesame as the above-described “C₆₋₁₀ aryl group”. It preferably includes a“C₆ arylsulfinyl group”. Specific examples thereof include, for example,phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl, and the like.

The “C₆₋₁₀ aryl” moiety in a “C₆₋₁₀ arylsulfonyl group” is defined thesame as the above-described “C₆₋₁₀ aryl group”. It preferably includes a“C₆ arylsulfonyl group”. Specific examples thereof include, for example,phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, and the like.

A “C₆₋₁₀ aryloxycarbonyl group” means a group having the above-described“C₆₋₁₀ aryloxy group” bound to a carbonyl group. It preferably includesa “C₆ aryloxycarbonyl group” (a phenyloxycarbonyl group). Specificexamples of the “C₆₋₁₀ aryloxycarbonyl group” include, for example,phenoxycarbonyl, 1-naphthoxycarbonyl, 2-naphthoxycarbonyl, and the like.

Examples of “an optionally substituted amino group” include amino, mono-or di-substituted amino.

Examples of the “mono- or di-substituted amino” include “C₁₋₆ alkyl”,“C₃₋₁₀ cycloalkyl”, “C₃₋₁₀ cycloalkyl C₁₋₄ alkyl”, “C₃₋₇ cycloalkyl C₁₋₄alkoxycarbonyl”, “C₁₋₄ alkylcarbonyl”, “C₁₋₄ alkoxycarbonyl”, “a 4- to7-membered saturated heterocycle”, “4- to 7-membered saturatedheterocyclyl C₁₋₄ alkyl”, “4- to 7-membered saturated heterocyclylcarbonyl”, “4- to 7-membered saturated heterocyclyloxycarbonyl”, “4- to7-membered saturated heterocyclyl C₁₋₄ alkylcarbonyl”, “C₆₋₁₀ aryl”,“C₇₋₁₄ aralkyl”, “C₆₋₁₀ arylcarbonyl”, “C₆₋₁₀ aryloxycarbonyl”, “5- or6-membered monocyclic heteroaryl”, “5- or 6-membered monocyclicheteroaryl C₁₋₄ alkyl”, and the like.

Specific examples of the “mono-substituted amino” include, for example,“mono-C₁₋₆ alkylamino” (e.g., methylamino, ethylamino, propylamino,1-methylethylamino, butylamino, 2-methylpropylamino,1-methylpropylamino, 1,1-dimethylethylamino, and the like);

“C₃₋₈ cycloalkylamino” (e.g., cyclopropylamino, cyclobutylamino,cyclopentylamino, cyclohexylamino, cycloheptylamino, and the like);“(C₃₋₈ cycloalkylC₁₋₄ alkyl)amino” (e.g., cyclopropylmethylamino,cyclobutylmethylamino, cyclopentylmethylamino, cyclohexylmethylamino,cycloheptylmethylamino, and the like);“(C₃₋₈ cycloalkylC₁₋₄ alkoxycarbonyl)amino” (e.g.,cyclopropoxycarbonylamino, cyclobutoxycarbonylamino,cyclopentoxycarbonylamino, cyclohexyloxycarbonylamino,cycloheptyloxycarbonylamino, and the like);“(C₁₋₄ alkylcarbonyl)amino” (e.g., methylcarbonylamino,ethylcarbonylamino, propylcarbonylamino, 1-methylpropylcarbonylamino,2-methylpropylcarbonylamino, butylcarbonylamino,2,2-dimethylethylcarbonylamino, and the like);“(C₁₋₄ alkoxycarbonyl)amino” (e.g., methoxycarbonylamino,ethoxycarbonylamino, propoxycarbonylamino, 1-methylpropoxycarbonylamino,2-methylpropoxycarbonylamino, butoxycarbonylamino,2,2-dimethylethoxycarbonylamino, and the like);“C₅₋₁₀ arylamino” (e.g., phenylamino, 1-naphthylamino, 2-naphthylamino,and the like);“C₇₋₁₄ aralkylamino” (e.g., benzylamino, 1-naphthylmethylamino,2-naphthylmethylamino, and the like);“C₆₋₁₀ arylcarbonylamino” (e.g., phenylcarbonylamino,1-naphthylcarbonylamino, 2-naphthylcarbonylamino, and the like);“C₆₋₁₀ aryloxycarbonylamino” (e.g., phenoxycarbonylamino,1-naphthoxycarbonylamino, 2-naphthoxycarbonylamino, and the like);“3- to 8-membered saturated heterocyclyl-amino” (e.g.,tetrahydropyranylamino, tetrahydropyridinylamino, pyrrolidinylamino,oxopyrrolidinylamino, tetrahydrofuranylamino, piperidinylamino, and thelike);“(3- to 8-membered saturated heterocyclyl C₁₋₄ alkyl)amino” (e.g.,tetrahydropyranylmethylamino, tetrahydropyridinylmethylamino,pyrrolidinylmethylamino, oxopyrrolidinylmethylamino,tetrahydrofuranylmethylamino, piperidinylmethylamino,piperazinylmethylamino, morpholinylmethylamino, and the like);“3- to 8-membered saturated heterocyclyl carbonylamino” (e.g.,tetrahydropyranylcarbonylamino, tetrahydropyridinylcarbonylamino,pyrrolidinylcarbonylamino, oxopyrrolidinylcarbonylamino,tetrahydrofuranylcarbonylamino, piperidinylcarbonylamino, and the like);“3- to 8-membered saturated heterocyclyloxycarbonylamino” (e.g.,tetrahydropyranyloxycarbonylamino, tetrahydropyridinyloxycarbonylamino,pyrrolidinyloxycarbonylamino, oxopyrrolidinyloxycarbonylamino,tetrahydrofuranyloxycarbonylamino, piperidinyloxycarbonylamino, and thelike);“(5- or 6-membered monocyclic heteroaryl)amino” (e.g., pyrrolylamino,thienylamino, furylamino, oxazolylamino, triazolylamino,isoxazolylamino, isothiazolylamino, imidazolylamino, pyrazolylamino,triazolylamino, oxadiazolylamino, thiadiazolylamino, tetrazolylamino,pyridylamino, pyrazylamino, pyrimidylamino, pyridazylamino,triazinylamino, and the like);“(5- or 6-membered monocyclic heteroaryl C₁₋₄ alkyl)amino” (e.g.,pyrrolylmethylamino, thienylmethylamino, furylmethylamino,oxazolylmethylamino, thiazolylmethylamino, isoxazolylmethylamino,isothiazolylmethylamino, imidazolylmethylamino, pyrazolylmethylamino,triazolylmethylamino, oxadiazolylmethylamino, thiadiazolylmethylamino,tetrazolylmethylamino, pyridylmethylamino, pyrazylmethylamino,pyrimidylmethylamino, pyridazylmethylamino, triazinylmethylamino, andthe like); and the like.

Specific examples of the “di-substituted amino” include, for example,

“di-C₁₋₆ alkylamino” (e.g., dimethylamino, diethylamino, dipropylamino,di-1-methylethylamino, dibutylamino, di-2-methylpropylamino,di-1-methylpropylamino, di-1,1-dimethylethylamino, and the like);“N—(C₁₋₆ alkyl)-N—(C₃₋₁₀ cycloalkyl)amino” (e.g.,methylcyclopropylamino, methylcyclobutylamino, methylcyclopentylamino,methylcyclohexylamino, methylcycloheptylamino, and the like);“N—(C₁₋₆ alkyl)-N-(4- to 7-membered saturated heterocyclyl)amino” (e.g.,methyltetrahydropyranylamino, methyltetrahydropyridinylamino,methylpyrrolidinylamino, methyloxopyrrolidinylamino,methyltetrahydrofuranylamino, methylpiperidinylamino, and the like); andthe like.

Examples of the “3- to 8-membered cyclic amino” include 3- to 8-memberedmonocyclic cyclic amino having one to three heteroatoms that areidentical or different and are selected from a nitrogen atom, an oxygenatom, or a sulfur atom. It is preferably a 5- to 6-membered monocycliccyclic amino group. In the “3- to 8-membered cyclic amino”, a bond onthe “group” will be from a nitrogen atom constituting a ring. Specificexamples of the “3- to 8-membered cyclic amino” include, for example,azetidino, pyrrolidino, imidazolidino, oxazolidino, thiazolidino,piperazino, piperidino, morpholino, thiomorpholino, azepano, oxoazepano,and the like. It is noted that the group encompasses cyclic amino ofwhich the ring contains a partially unsaturated bond.

The “3- to 8-membered cyclic amino” or “5- or 6-membered cyclic amino”may form a fused ring with C₃₋₆ cycloalkyl, 6-membered aromatichydrocarbon, or a 5- or 6-membered heterocycle. Specific examples ofcyclic amino forming such a fused ring include “groups” represented bythe following:

and the like.

An “aminocarbonyl group” means a group having the above-described “aminogroup” bound to a carbonyl group. In this regard, the “amino” means anunsubstituted amino group, a mono-substituted amino group, adi-substituted amino group, or 3- to 8-membered cyclic amino.

An “aminosulfinyl group” means a group having the above-described “aminogroup” bound to a sulfinyl group. In this regard, the “amino” means anunsubstituted amino group, a mono-substituted amino group, adi-substituted amino group, or 3- to 8-membered cyclic amino.

An “aminosulfonyl group” means a group having the above-described “aminogroup” bound to a carbonyl group. In this regard, the “amino” is anunsubstituted amino group, a mono-substituted amino group, adi-substituted amino group, or 3- to 8-membered cyclic amino.

The “aminocarbonyl” moiety in an “aminocarbonyloxy group” is defined thesame as the above-described “aminocarbonyl group”.

A “C₁₋₆ alkylaminocarbonyl group” means a group that is theabove-described “mono- or di-substituted amino” in which the amino groupsubstituted with one or two C₁₋₆ alkyl is bound to a carbonyl group.

The “C₁₋₆ alkylaminocarbonyl” moiety of a “C₁₋₆ alkylaminocarbonylaminogroup” is defined the same as the above-described “C₁₋₆alkylaminocarbonyl group”.

Examples of a substituent of “an optionally substituted C₁₋₆ alkylgroup” include:

(a) a halogen atom;(b) a cyano group;(c) a hydroxy group;(d) a formyl group;(e) a C₁₋₆ alkylcarbonyl group;(f) a C₁₋₆ alkylcarbonyloxy group;(g) a carboxy group;(h) amino (wherein the amino is optionally substituted with one or twogroups that are identical or different and are selected from the groupconsisting of(h1) C₁₋₆ alkyl (wherein the alkyl is optionally substituted with(h11) hydroxy,(h12) cyano,(h13) a halogen atom,(h14) amino (wherein the amino is optionally substituted with one or twoC₁₋₆ alkyl groups or C₁₋₆ alkylcarbonyl groups that are identical ordifferent),(h15) C₁₋₆ alkoxy,(h16) 5- or 6-membered monocyclic heteroaryl,(h17) a 4- to 7-membered saturated heterocycle, or(h18) a C₃₋₁₀ cycloalkylcarbonyl)(h2) C₃₋₁₀ cycloalkyl (wherein the ring is optionally substituted withC₁₋₆ alkyl),(h3) C₃₋₁₀ cycloalkyl C₁₋₄ alkyl,(h4) a 4- to 7-membered saturated heterocycle (wherein the ring isoptionally substituted with a halogen atom or C₁₋₆ alkyl),(h5) a 4- to 7-membered saturated heterocyclyl-C₁₋₄ alkyl,(h6) C₆₋₁₀ aryl (wherein the ring is optionally substituted with ahalogen atom or C₁₋₆ alkyl),(h7) C₇₋₁₄ aralkyl (wherein the ring is optionally substituted with ahalogen atom, C₁₋₆ alkyl, or C₁₋₆ alkoxy),(h8) a 5- or 6-membered monocyclic heteroaryl (wherein the ring isoptionally substituted with a halogen atom or C₁₋₆ alkyl), and(h9) 5- or 6-membered monocyclic heteroaryl C₁₋₄ alkyl);(i) C₁₋₆ alkoxy (wherein the group is optionally substituted with(i1) hydroxy,(i2) C₁₋₆ alkoxy (wherein the group is optionally substituted with oneto three fluorine atoms),(i3) C₃₋₁₀ cycloalkyl,(i4) 4- to 7-membered cyclic amino (wherein the group is optionallysubstituted with(i41) hydroxy,(i42) cyano,(i43) one to four fluorine atoms,(i44) C₁₋₆ alkyl (wherein the alkyl is optionally substituted with oneto three fluorine atoms or C₁₋₆ alkoxy)(i45) C₁₋₆ alkoxy (wherein the alkoxy is optionally substituted with oneto three C₆₋₁₀ aryl),(i46) formyl,(i47) C₁₋₆ alkylcarbonyl,(i48) C₁₋₆ alkylsulfonyl, or(i49) oxo),(i5) a 4- to 7-membered saturated heterocycle (wherein the heterocycleis optionally substituted with a group selected from the above-described(i41)-(i49)),(i6) 5- or 6-membered monocyclic heteroaryl (wherein the ring isoptionally substituted with a halogen atom or C₁₋₆ alkyl),(i7) C₆₋₁₀ aryl (wherein the group is optionally substituted with ahalogen atom, C₁₋₄ alkyl, or C₁₋₄ alkoxy),(i8) C₁₋₆ alkylcarbonylamino,(i9) amino (wherein the amino is optionally substituted with one or twogroups that are identical or different and are selected from the groupconsisting of C₁₋₆ alkyl (wherein the group is optionally substitutedwith hydroxy), C₃₋₁₀ cycloalkyl, and C₃₋₁₀ cycloalkyl C₁₋₄ alkyl),(i10) mono- or di-C₁₋₆ alkylaminocarbonyl,(i11) a halogen atom, or(i12) C₇₋₁₄ aralkyloxy);(j) a C₃₋₁₀ cycloalkyloxy group (wherein the ring is optionallysubstituted with C₁₋₆ alkyl);(k) an oxo group;(l) 5- or 6-membered monocyclic heteroaryl group (wherein the group isoptionally substituted with a halogen atom or C₁₋₆ alkyl);(m) a 4- to 7-membered saturated heterocycle (wherein the heterocycle isoptionally substituted with a group selected from the above-described(i41)-(i49));(n) an optionally substituted aminocarbonyl group;(o) an optionally substituted aminosulfonyl group;(p) an optionally substituted aminocarbonyloxy group;(q) a C₇₋₁₄ aralkyloxy group;(r) a 5- or 6-membered monocyclic heteroaryloxy group (wherein the ringis optionally substituted with a halogen atom or C₁₋₆ alkyl);(s) a 4- to 7-membered saturated heterocyclyloxy group (wherein the ringis optionally substituted with C₁₋₆ alkyl optionally substituted withone to three halogen atoms);(t) a C₁₋₆ alkylsulfonyl group;(u) a C₁₋₆ alkoxycarbonyl group;(v) a C₁₋₆ alkylsulfonyloxy group;(w) a C₁₋₆ alkoxycarbonylamino group;(x) a C₁₋₆ alkylcarbonylamino group (wherein the group is optionallysubstituted with(x1) hydroxy,(x2) a halogen atom,(x3) C₁₋₆ alkoxy, or(x4) C₁₋₆ alkylcarbonyloxy);(y) a 5- or 6-membered monocyclic heteroarylcarbonylamino group (whereinthe group is optionally substituted with C₁₋₆ alkyl);(z) a 4- to 7-membered saturated heterocyclylcarbonylamino group(wherein the group is optionally substituted with C₁₋₆ alkyl optionallysubstituted with one to three fluorine atoms);(aa) a mono- or di-C₁₋₆ alkylaminocarbonylamino group;(ab) a 4- to 7-membered cyclic amino group (wherein the ring isoptionally substituted with a group selected from the above-described(i41)-(i49)); and the like.

Examples of a substituent of “an optionally substituted C₁₋₆ alkenylgroup”, “an optionally substituted C₁₋₆ alkynyl group”, “an optionallysubstituted C₁₋₆ alkoxy group”, “an optionally substituted C₁₋₆alkylcarbonyl group”, “an optionally substituted C₁₋₆ alkylcarbonyloxygroup”, “an optionally substituted C₁₋₆ alkylcarbonylamino group”, “anoptionally substituted C₁₋₆ alkylthio group”, “an optionally substitutedC₁₋₆ alkylsulfinyl group”, “an optionally substituted C₁₋₆ alkylsulfonylgroup”, “an optionally substituted C₁₋₆ alkoxycarbonyl group”, “anoptionally substituted C₁₋₆ alkylamino group”, “an optionallysubstituted C₁₋₆ alkylaminocarbonyl group”, “an optionally substitutedC₁₋₆ alkylaminocarbonylamino group”, and “an optionally substituted C₁₋₆alkylaminocarbonylamino group” include: one group selected from thegroup consisting of the above-described (a) to (ab), which are examplesof a substituent of the “optionally substituted C₁₋₆ alkyl group”; andthe like.

Examples of a substituent of “an optionally substituted C₃₋₁₀ cycloalkylgroup”, “an optionally substituted C₃₋₁₀ cycloalkyloxy group”, “anoptionally substituted C₃₋₁₀ cycloalkylthio group”, “an optionallysubstituted C₃₋₁₀ cycloalkylsulfinyl group”, “an optionally substitutedC₃₋₁₀ cycloalkylsulfonyl group”, “an optionally substituted C₃₋₁₀cycloalkyloxycarbonyl group”, “an optionally substituted 3- to8-membered heterocyclic group”, “an optionally substituted 3- to8-membered heterocyclyloxy group”, “an optionally substituted 3- to8-membered heterocyclyloxycarbonyl group”, “an optionally substituted 3-to 8-membered heterocyclylsulfinyl group”, “an optionally substituted 3-to 8-membered heterocyclylsulfonyl group”, “3- to 8-membered cyclicamino group”, “3- to 8-membered cyclic aminocarbonyl group”, “3- to8-membered cyclic aminosulfinyl group”, and “3- to 8-membered cyclicaminosulfonyl group” include: one group selected from the groupconsisting of the above-described (a) to (ab), which are examples of asubstituent of the “optionally substituted C₁₋₆ alkyl group”, and C₁₋₄alkyl; and the like. It is noted that a ring of the substituent (e.g.,cycloalkyl, cyclic amino, and the like) is optionally substituted withoxo or thioxo.

Examples of a substituent of “an optionally substituted C₆₋₁₀ arylgroup”, “an optionally substituted C₆₋₁₀ aryloxy group”, “an optionallysubstituted C₆₋₁₀ arylcarbonyl group”, “an optionally substituted C₆₋₁₀aryloxycarbonyl group”, “an optionally substituted C₆₋₁₀ arylthiogroup”, “an optionally substituted C₆₋₁₀ arylsulfinyl group”, “anoptionally substituted C₆₋₁₀ arylsulfonyl group”, “an optionallysubstituted 5- or 6-membered monocyclic heteroaryl group”, “anoptionally substituted 5- or 6-membered monocyclic heteroaryloxy group”,“an optionally substituted 5- or 6-membered monocyclicheteroarylcarbonyl group”, “an optionally substituted 5- or 6-memberedmonocyclic heteroaryloxycarbonyl group”, “an optionally substituted 5-or 6-membered monocyclic heteroarylthio group”, “an optionallysubstituted 5- or 6-membered monocyclic heteroarylsulfinyl group”, and“an optionally substituted 5- or 6-membered monocyclicheteroarylsulfonyl group” include:

(a2) a halogen atom;(b2) a cyano group;(c2) an optionally substituted C₁₋₆ alkyl group;(d2) C₁₋₆ alkylsulfonyl group (wherein the group is optionallysubstituted with(d21) a halogen atom,(d22) hydroxy,(d23) C₁₋₆ alkoxy,(d24) C₃₋₁₀ cycloalkyl,(d25) C₃₋₁₀ cycloalkyloxy,(d26) di-C₁₋₆ alkylamino,(d27) 4- to 7-membered cyclic amino, or(d28) 4- to 7-membered saturated heterocycle);(e2) an amino group (wherein the amino is optionally substituted withone or two groups that are identical or different and are selected fromthe group consisting of the above-described (h1) to (h9));(f2) an aminosulfonyl group (wherein the amino is optionally substitutedwith one or two C₁₋₆ alkyl groups that are identical or different(wherein the alkyl is optionally substituted with a halogen atom,hydroxy, C₁₋₄ alkoxy, or di-C₁₋₆ alkylamino));(g2) a 4- to 7-membered cyclic amino group (wherein the ring isoptionally substituted with the above-described (i1) to (i12));(h2) an aminocarbonyl group (wherein the amino group is optionallysubstituted with one or two groups that are identical or different andare selected from the group consisting of the (h1) to (h9));(i2) a 4- to 7-membered saturated heterocycle (wherein the ring isoptionally substituted with a group selected from the group consistingof the above-described (i1) to (i12));(j2) a carboxy group;(k2) a C₁₋₆ alkoxy group (wherein the group is optionally substitutedwith a group selected from the group consisting of the above-described(i1) to (i12));(l2) C₃₋₁₀ cycloalkyloxy group;(m2) a 4- to 7-membered saturated heterocyclyloxy group (wherein thering is optionally substituted with a group selected from the groupconsisting of the above-described (i1) to (i12));(n2) a C₇₋₁₄ aralkyloxy group;(o2) a C₁₋₆ alkoxycarbonyl group (wherein the group is optionallysubstituted with a group selected from the group consisting of theabove-described (i1) to (i12));(p2) a C₁₋₆ alkylcarbonylamino group (wherein the amino is optionallysubstituted with C₁₋₆ alkyl, and the alkyl is optionally substitutedwith a group selected from the group consisting of the above-described(d21) to (d28);(q2) a C₃₋₁₀ cycloalkylcarbonylamino group (wherein the amino isoptionally substituted with C₁₋₆ alkyl);(r2) a 5- or 6-membered monocyclic heteroarylcarbonylamino group(wherein the amino is optionally substituted with C₁₋₆ alkyl);(s2) a 4- to 7-membered saturated heterocyclylcarbonylamino group(wherein the amino is optionally substituted with C₁₋₆ alkyl, and thering is optionally substituted with a group selected from the groupconsisting of the above-described (i1) to (i12));(t2) a mono- or di-C₁₋₆ alkylaminocarbonylamino group (wherein the aminois optionally substituted with C₁₋₆ alkyl);(u2) C₁₋₆ alkoxycarbonylamino group (wherein the amino is optionallysubstituted with C₁₋₆ alkyl, and the alkoxy is optionally substitutedwith a group selected from the group consisting of the above-described(i1) to (i12));(v2) a C₆₋₁₀ aryl group;(w2) a 5- or 6-membered monocyclic heteroaryl group; and the like.

Preferred embodiments of the present invention are further described.

In the present specification, formula (1) is an isomer having arelationship with the following formula (1′) between an oxidant and areductant that can attain equilibrium. They can be considered as beingsynonymous.

It is preferable that “A” is an oxygen atom or a sulfur atom.

It is preferable that “ring G” is the following formulas (a) to (h):

It is more preferable that “ring G” is the following formulas (a) to(f):

It is further preferable that “ring G” is the following formulas (a) to(d):

It is further preferable that “ring G” is the following formula (e) or(f):

It is preferable that “R¹” is a hydrogen atom or a C₁₋₆ alkylcarbonylgroup (wherein the alkyl is optionally substituted with 3- to 8-memberedcyclic amino).

It is preferable that “R²” is a hydrogen atom.

It is preferable that all of “R³”, “R⁴”, and “R⁵” are hydrogen atoms.

It is preferable that “R⁶” is a hydrogen atom.

Preferred embodiments of the present invention encompass compoundsrepresented by the following formulas (1a) to (1p).

(1) A compound represented by the following formula (1a) or apharmacologically acceptable salt thereof:

[each symbol in the formula is defined the same as item 1]. Preferredembodiments of respective symbols in the compound represented by theabove formula (1a) are the same as the preferred embodiments in thecompound represented by formula (1).

(2) A compound represented by the following formula (1b) or apharmacologically acceptable salt thereof:

[each symbol in the formula is defined the same as item 1]. Preferredembodiments of respective symbols in the compound represented by theabove formula (1b) are the same as the preferred embodiments in thecompound represented by formula (1).

(3) A compound represented by the following formula (1c) or apharmacologically acceptable salt thereof:

[each symbol in the formula is defined the same as item 1]. Preferredembodiments of respective symbols in the compound represented by theabove formula (1c) are the same as the preferred embodiments in thecompound represented by formula (1).

(4) A compound represented by the following formula (1d) or apharmacologically acceptable salt thereof:

[each symbol in the formula is defined the same as item 1]. Preferredembodiments of respective symbols in the compound represented by theabove formula (1d) are the same as the preferred embodiments in thecompound represented by formula (1).

(5) A compound represented by the following formula (1e) or apharmacologically acceptable salt thereof:

[each symbol in the formula is defined the same as item 1]. Preferredembodiments of respective symbols in the compound represented by theabove formula (1e) are the same as the preferred embodiments in thecompound represented by formula (1)

(6) A compound represented by the following formula (1f) or apharmacologically acceptable salt thereof:

[each symbol in the formula is defined the same as item 1]. Preferredembodiments of respective symbols in the compound represented by theabove formula (1f) are the same as the preferred embodiments in thecompound represented by formula (1)

(7) A compound represented by the following formula (1 g) or apharmacologically acceptable salt thereof:

[each symbol in the formula is defined the same as item 1]. Preferredembodiments of respective symbols in the compound represented by theabove formula (1 g) are the same as the preferred embodiments in thecompound represented by formula (1).

(8) A compound represented by the following formula (1h) or apharmacologically acceptable salt thereof:

[each symbol in the formula is defined the same as item 1]. Preferredembodiments of respective symbols in the compound represented by theabove formula (1h) are the same as the preferred embodiments in thecompound represented by formula (1).

(9) A compound represented by the following formula (1i) or apharmacologically acceptable salt thereof:

[each symbol in the formula is defined the same as item 1]. Preferredembodiments of respective symbols in the compound represented by theabove formula (1i) are the same as the preferred embodiments in thecompound represented by formula (1).

(10) A compound represented by the following formula (1j) or apharmacologically acceptable salt thereof:

[each symbol in the formula is defined the same as item 1]. Preferredembodiments of respective symbols in the compound represented by theabove formula (1j) are the same as the preferred embodiments in thecompound represented by formula (1)

(11) A compound represented by the following formula (1k) or apharmacologically acceptable salt thereof:

[each symbol in the formula is defined the same as item 1]. Preferredembodiments of respective symbols in the compound represented by theabove formula (1k) are the same as the preferred embodiments in thecompound represented by formula (1).

(12) A compound represented by the following formula (1l) or apharmacologically acceptable salt thereof:

[each symbol in the formula is defined the same as item 1]. Preferredembodiments of respective symbols in the compound represented by theabove formula (1l) are the same as the preferred embodiments in thecompound represented by formula (1)

(13) A compound represented by the following formula (1m) or apharmacologically acceptable salt thereof:

[each symbol in the formula is defined the same as item 1]. Preferredembodiments of respective symbols in the compound represented by theabove formula (1m) are the same as the preferred embodiments in thecompound represented by formula (1).

(14) A compound represented by the following formula (1n) or apharmacologically acceptable salt thereof:

[each symbol in the formula is defined the same as item 1]. Preferredembodiments of respective symbols in the compound represented by theabove formula (1n) are the same as the preferred embodiments in thecompound represented by formula (1)

(15) A compound represented by the following formula (1o) or apharmacologically acceptable salt thereof:

[each symbol in the formula is defined the same as item 1]. Preferredembodiments of respective symbols in the compound represented by theabove formula (1o) are the same as the preferred embodiments in thecompound represented by formula (1).

(16) A compound represented by the following formula (1p) or apharmacologically acceptable salt thereof:

[each symbol in the formula is defined the same as item 1]. Preferredembodiments of respective symbols in the compound represented by theabove formula (1p) are the same as the preferred embodiments in thecompound represented by formula (1).

A “pharmacologically acceptable salt” includes acid addition salts andbase addition salts. Examples of acid addition salts include: inorganicacid salts such as hydrochlorides, hydrobromides, sulfates,hydroiodides, nitrates, phosphates, and the like; and organic acid saltssuch as citrate, oxalate, phthalate, fumarate, maleate, succinate,malate, acetate, formate, propionate, benzoate, trifluoroacetate,methanesulfonate, benzenesulfonate, p-toluenesulfonate,camphorsulfonate, and the like; and examples of base addition saltsinclude inorganic base salts such as sodium, potassium, calcium,magnesium, barium, and aluminum salts, and the like, organic base saltssuch as trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine,ethanolamine, diethanolamine, triethanolamine, tromethamine[tris(hydroxymethyl)methylamine], t-butylamine, cyclohexylamine,dicyclohexylamine, and N,N-dibenzylethylamine, and the like, and furthersalts of an amino acid such as basic and acidic amino acids includingarginine, lysine, ornithine, aspartic acid, glutamic acid, and the like.

Suitable salts and pharmaceutically acceptable salts of startingcompounds and target compounds are conventional nontoxic salts. Theyinclude acid addition salts such as organic acid salts (e.g., acetate,trifluoroacetate, maleate, fumarate, citrate, tartrate,methanesulfonate, benzenesulfonate, formate, p-toluenesulfonate, or thelike) and inorganic acid salts (e.g., hydrochloride, hydrobromide,hydroiodide, sulfate, nitrate, phosphate, or the like), salts with anamino acid (e.g., arginine, aspartic acid, glutamic acid, or the like),metal salts such as alkali metal salts (e.g., sodium salt, potassiumsalt, or the like), alkali earth metal salts (e.g., calcium salt,magnesium salt, or the like), and the like, ammonium salts, organic basesalts (e.g., trimethylamine salts, triethylamine salts, pyridine salts,picoline salts, dicyclohexylamine salts, N,N′-dibenzylethylene diaminesalts, or the like), or the like, and additionally those skilled in theart can appropriately select them.

When it is desired to obtain a salt of the present compound, if thepresent compound is obtained in a salt form, it may be purified as itis, or if it is obtained in free form, it may be dissolved or suspendedin a suitable organic solvent, and an acid or a base is added thereto toform a salt in accordance with a general method.

In addition, although the present compounds and pharmacologicallyacceptable salts thereof may exist in an adduct form with water or anykind of solvent, these adducts are also encompassed by the presentinvention.

In addition, the present invention encompasses compounds represented byformula (1) or prodrugs thereof, or pharmacologically acceptable saltsthereof. It also encompasses hydrates or solvates (such as ethanolsolvates and the like) thereof. Further, the present inventionencompasses all tautomers and all present stereoisomers of the presentcompound (1) as well as those in all modes of crystal forms.

The term “a prodrug of a compound of formula (1)” in the presentspecification means a compound that is converted to a compound offormula (1) by reaction with an enzyme, gastric acid, or the like underphysiological condition in vivo, for example, a compound that isconverted to a compound of formula (1) by enzymatic oxidation,reduction, hydrolysis, or the like.

Among the present compounds (1), there are compounds that may exist asenantiomers based on an optically-active center, atropisomers based onaxial or planar chirality caused by restriction of intramolecularrotation, other stereoisomers, tautomers, geometric isomer, and thelike. However, all possible isomers and mixtures thereof, includingthese, are encompassed within the scope of the present invention.

In particular, an enantiomer and an atropisomer can be obtained as aracemic body, or an optically-active substance when an optically-activestarting material or intermediate is used, respectively. If necessary,in an appropriate step of the above-described production method, acorresponding starting material, intermediate, or racemic body as afinal product can be physically or chemically resolved into theiroptical enantiomers by a known separation method, such as a method usingan optically active column, a fractional crystallization method, or thelike. Specifically, for example, in a diastereomer method, two types ofdiastereomers are formed from a racemic body by reaction using anoptical active resolving agent. Since these different diastereomersgenerally have different physical properties, they can be separated by aknown method such as fractional crystallization and the like.

Hereinafter, production methods of compounds represented by formula (1)in the present invention are described. Compounds represented by formula(1) or pharmacologically acceptable salts thereof (hereinafter sometimesreferred to as “the present compound(s)”) are described with examples.However, the scope of present invention is certainly not limited tothese examples.

A compound of the present invention represented by formula (1) or a saltthereof can be produced from a known compound, for example, thefollowing production methods: Methods 1 to 14, and methods in accordancetherewith, or by appropriately combining synthesis methods well-known tothose skilled in the art.

It is noted that a compound in a reaction includes the case where itforms a salt, for example, salts similar to salts in compound (1) andthe like are used as such a salt.

In addition, a compound obtained in each step can be used in a nextreaction as a reaction solution or as a composition. However, it can beisolated from a reaction mixture in accordance with a routine method,and readily purified by a separation means such as recrystallization,distillation, chromatography, and the like.

Each symbol of compounds in the following reactions is defined the sameas above, unless specifically indicated.

Production Method 1:

(In the formulas, A, R¹, R², R³, R⁴, R⁵, R⁷, R⁸, and G are defined thesame as the above-described item 21.)

To this step 1, a method described in literature [for example, EuropeanJournal of Organic Chemistry, 3876, vol. 20, (2010), Tetrahedron, 4213,vol. 57, (2001), Journal of Medicinal Chemistry, 7273, vol. 55, (2012,ACS Applied Materials & Interfaces, 3994, vol. 4, (2012), and the like]is applied, and Compound (1-2) can be produced from Compound (1-1).

It is noted that in the present invention, this method is applied tocompound (1-1) where ring G is a saturated heterocycle, and however,until now, there has been no report that this method has been applied tothe production of the heterocyclic compound (1-2).

Compound (1-2) can be produced by reacting it, in solvent in thepresence of an oxidant, with (1-1) obtained by a known synthesis methodor the following production method. Organic solvent includes aproticsolvent (N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethylsulfoxide, acetonitrile, propionitrile, and the like), ether typesolvent (tetrahydrofuran, 1,4-dioxane, and the like), halogenatedhydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane,chlorobenzene, and the like), hydrocarbons (toluene, benzene, and thelike), water, mixed solvents thereof, and the like, and suitably a mixedsolvent of acetonitrile and water. The following can be used asoxidants: metal type oxidants [osmium tetraoxide, potassiumpermanganate, silver(II) picolinate, ammonium hexanitratocerate(IV),benzeneseleninic acid, bis(4-methoxyphenyl) selenoxide,bis(tetrabutylammonium) dichromate, lead tetraacetate, phosphomolybdicacid hydrate, pyridinium chlorochromate, pyridinium dichromate,pyridinium fluorochromate, quinolinium dichromate, silver(II)pyridine-2-carboxylate, tetrapropylammonium perruthenate, and the like],hypervalent iodine oxidants [(2-iodoxybenzoic acid, Dess-Martinperiodinane, 1-(tert-butylperoxy)-1,2-benziodoxol-3-(1H)-one,bis(pyridine)iodonium tetrafluoroborate, iodosobenzene, iodomesitylenediacetate, {hydroxy(tosyloxy)iodo}benzene,poly{4-(diacetoxyiodo)styrene}, (diacetoxyiodo)benzene,bis(trifluoroacetoxy)iodobenzene,{bis(trifluoroacetoxy)iodo}pentafluorobenzene, and the like],N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, and thelike, and suitably, ammonium hexanitratocerate(IV),(diacetoxyiodo)benzene, N-bromosuccinimide, and the like. The amount ofan oxidant used is, generally, 2 to 10 mol, preferably, to 3 mol per molof compound (1-1). A reaction time is, generally, about 0.5 to about 48hours, preferably, about 0.5 to about 12 hours. A reaction temperatureis, generally, about −20 to about 180° C., preferably, about 0 to about100° C.

Production Method 2:

(In the formulas, A, R⁷, and R⁸ are defined the same as above. R⁹ isC₁₋₆ alkyl.)

This step 1 can produce compound (2-3) from compound (2-1) in accordancewith a similar method to methods and the like described in literature[for example, Heterocycles, 1913, vol. 75, (2008), Journal of MedicinalChemistry, 1819, vol. 53, (2010), Journal of the Chilean ChemicalSociety, 14, vol. 54, (2009), Molecules, 1388, vol. 17, (2012),Bioorganic & Medicinal Chemistry Letters, 4961, vol. 15, (2005),Synlett, 670, vol. 5, (2001), and the like].

A solvent used in this step 1 may be any solvent as long as it isinactive in the reaction, and although it is not particularly limited,for example, THF, 1,4-dioxane, DME, benzene, toluene, xylene, DMF, DMA,NMP, and the like can be used alone or after mixing them. Among others,THF or DMF is preferred.

As a base, for example, basic salts such as sodium carbonate, potassiumcarbonate, cesium carbonate, sodium acetate, sodium hydride, calciumhydride, and the like, aromatic amines such as pyridine, lutidine, andthe like, tertiary amines such as triethylamine, tripropylamine,tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine,N,N-diisopropylethylamine, N,N-dimethylaniline, N-methylpiperidine,N-methylpyrrolidine, N-methylmorpholine, and the like can be used. Amongothers, potassium carbonate or sodium hydride is preferred.

A reaction is performed from at a temperature between room temperatureand the boiling point of a solvent used, preferably, 0 to 80° C.,generally, for 0.5 to 24 hours.

Production Method 3

(In the formulas, A, R⁷, R⁸, and R⁹ are defined the same as above.)

This step 1 can produce compound (3-3) from compound (3-1) in accordancewith a similar method to methods and the like described in literature[for example, Tetrahedron, 12227, vol. 55, (1999), Journal of OrganicChemistry, 4692, vol. 76, (2011), Journal of Heterocyclic Chemistry,683, vol. 49, (2012), and the like].

Production Method 4:

(In the formulas, R¹, R², R⁷, R⁸, and A are defined the same as above.)

This step 1 can produce compound (4-2) and compound (4-3) from compound(4-1) in accordance with a similar method to methods and the likedescribed in literature [for example, Organic Letters, 2157, vol. 7,(2005), Journal of Medicinal Chemistry, 7574, vol. 56, (2013),Bioorganic & Medicinal Chemistry Letters, 138, vol. 22, (2012), KhimiyaGeterotsiklicheskikh Soedinenii, 27, vol. 1, (1980), and the like].

Production Method 5:

(In the formulas, R¹, R², R³, R⁴, R⁷, R⁸, and A are defined the same asabove.)

These steps (1 to 3) can produce compound (5-4) from compound (4-2) inaccordance with similar methods to methods and the like described inliterature [for example, Bioorganic & Medicinal Chemistry Letters, 806,vol. 22, 2012 Journal of Medicinal Chemistry, 7574, vol. 56, (2013),Khimiya Geterotsiklicheskikh Soedinenii, 27, vol. 1, (1980), Synlett,1781, vol. 11, (2009), Tetrahedron Letters, 5452, vol. 52, (2011),Bulletin of the Chemical Society of Japan, 891, vol. 70, (1997),Synlett, 116, vol. 1, (2011), Tetrahedron, 4612, vol. 69, (2013),Tetrahedron Letters, 5145, vol. 52, (2011), Chemistry Letters, 1422,vol. 36, (2007), European Journal of Organic Chemistry, 4039, vol. 19,(2004), Tetrahedron, 2755, vol. 64, (2008), and the like].

Production Method 6:

(In the formulas, R¹, R², R⁷, R⁸, and A are defined the same as above.)

This step can produce compound (6-1) and compound (6-2) from compound(4-1) in accordance with a similar method to methods and the likedescribed in literature [for example, Physiological Zoology, 312, vol.36, (1963), European Journal of Medicinal Chemistry, 4827, vol. 46,(2011), Synthetic Metals, 2491, vol. 159, (2009), Journal of theAmerican Chemical Society, 4466, vol. 132, (2010), Bulletin of theChemical Society of Japan, 4464, vol. 61, (1988), and the like].

Production Method 7:

(In the formulas, R¹, R², R³, R⁴, R⁷, R⁸, R⁹, and A are defined the sameas above. R¹⁰ is C₁₋₆ alkyl.)

These steps (1 to 3) can produce compound (7-4) from compound (6-1) inaccordance with similar methods to methods and the like described inliterature [for example, Journal of Organic Chemistry, 5026, vol. 78,(2013), Tetrahedron, 5787, vol. 62, (2006), Tetrahedron Letters, 8527,vol. 38, (1997), Indian Journal of Chemistry, Section B: OrganicChemistry Including Medicinal Chemistry, 72, vol. 25B, (1986), and thelike].

Production Method 8

[In the formulas, R¹, R², R³, R⁴, R⁷, R⁸, and A are defined the same asabove. X represents a leaving group (e.g., a chlorine atom, a bromineatom, an iodine atom, methoxy, ethoxy, propoxy, butoxy, imidazole,pyrrole, optionally substituted phenoxy, and the like).]

These steps (1 to 4) can produce compound (8-6) from compound (6-1) inaccordance with similar methods to methods and the like described inliterature [for example, Compt. Rend., 1265, vol. 120, (1895), Journalof Organic Chemistry, 1418, vol. 68, (2003), Journal of the AmericanChemical Society, 3554, vol. 77, (1955), Journal of Organic Chemistry,2353, vol. 60, (1995), Journal of Organic Chemistry, 3742, vol. 46,(1981), Tetrahedron: Asymmetry, 1395, vol. 22, (2011), Journal ofMedicinal Chemistry, 8287, vol. 53, (2010), Tetrahedron, 11020, vol. 64,(2008), Tetrahedron: Asymmetry, 2281, vol. 6, (1995), Journal of OrganicChemistry, 650, vol. 14, (1949), Polish Journal of Chemistry, 1317, vol.75, (2001), and the like].

Production Method 9:

(In the formulas, R¹, R², R³, R⁴, R⁵, R⁷, R⁸, and A are defined the sameas above.)

These steps (1 to 2) can produce compound (9-3) from compound (4-3) inaccordance with similar methods to methods and the like described inliterature [for example, Bulletin of the Chemical Society of Japan, 891,vol. 70, (1997), Tetrahedron Letters, 1783, vol. 47, (2006),Tetrahedron, 1763, vol. 67, (2011), Tetrahedron Letters, 6869, vol. 50,(2009), Synlett, 449, vol. 3, (2004), Heterocycles, 2631, vol. 60,(2003), Tetrahedron, 3259, vol. 42, (1986), Journal of MedicinalChemistry, 1832, vol. 28, (1985), and the like].

Production Method 10:

(In the formulas, R¹, R², R³, R⁴, R⁷, R⁸, and A are defined the same asabove.)

These steps (1 to 3) can produce compound (10-4) from compound (4-1) inaccordance with similar methods to methods and the like described inliterature [for example, European Journal of Medicinal Chemistry, 611,vol. 24, (1989), Heterocycles, 1623, vol. 34, (1992), European Journalof Medicinal Chemistry, 611, vol. 24, (1989), Journal of MedicinalChemistry, 614, vol. 33, (1990), Asian Journal of Chemistry, 5575, vol.22, (2010), Journal of the American Chemical Society, 8227, vol. 135,(2013), Journal of Organic Chemistry, 2548, vol. 73, (2008), Journal ofOrganic Chemistry, 6599, vol. 72, (2007), Bioorganic & MedicinalChemistry Letters, 3771, vol. 14, (2004), Russian Chemical Bulletin,414, vol. 58, (2010), Collection of Czechoslovak ChemicalCommunications, 285, vol. 49, (1984), and the like].

Production Method 11:

(In the formulas, R³, R⁴, R⁵, R⁷, R⁸, A, and G are defined the same asabove.)

This step can produce compounds (11-2) and (11-3) from compound (11-1)in accordance with a similar method to methods and the like described inliterature [for example, Physiological Zoology, 312, vol. 36, (1963),European Journal of Medicinal Chemistry, 4827, vol. 46, (2011),Synthetic Metals, 2491, vol. 159, (2009), Journal of the AmericanChemical Society, 4466, vol. 132, (2010), Bulletin of the ChemicalSociety of Japan, 4464, vol. 61, (1988), and the like].

Production Method 12:

(In the formula, R³, R⁴, R⁵, R⁷, R⁸, R⁹, A, and G are defined the sameas above.)

These steps (1 to 2) can produce compound (12-3) from compound (11-2) inaccordance with similar methods to methods and the like described inliterature [for example, Organic Letters, 2157, vol. 7, (2005), Journalof Medicinal Chemistry, 7574, vol. 56, (2013), Bioorganic & MedicinalChemistry Letters, 138, vol. 22, (2012), Khimiya GeterotsiklicheskikhSoedinenii, 27, vol. 1, (1980), Heterocycles, 1913, vol. 75, (2008),Journal of Medicinal Chemistry, 1819, vol. 53, (2010), Journal of theChilean Chemical Society, 14, vol. 54, (2009), Molecules, 1388, vol. 17,(2012), Bioorganic & Medicinal Chemistry Letters, 4961, vol. 15, (2005),Synlett, 670, vol. 5, (2001), and the like].

Production Method 13:

[In the formulas, R¹, R², R³, R⁴, R⁵, A, and G are defined the same asabove. L¹ and L² represent hydrogen, a hydroxyl group, or a leavinggroup (e.g., a chlorine atom, a bromine atom, an iodine atom,methanesulfonyloxy, tri fluoromethanesulfonyloxy, p-toluenesulfonyloxy,or the like).]

Step 1

In this step 1, compound (10-3) can be produced by reacting, in anorganic solvent in the presence of a base, (13-1) obtained as acommercially available product or in accordance with a known method [forexample, Journal of Medicinal Chemistry, 1329, vol. 29, (1986), EuropeanJournal of Medicinal Chemistry, 3938, vol. 45, (2010), Bioorganic &Medicinal Chemistry Letters, 952, vol. 21, (2011), European Journal ofOrganic Chemistry, 4201, vol. 18, (2006), Journal of Organic Chemistry,5026, vol. 78, (2013), and the like], with (13-2) obtained as acommercially available product or in accordance with a known synthesismethod [for example, Bioorganic & Medicinal Chemistry, 5705, vol. 20,(2012), Journal of American Chemical Society, 3460, vol. 103, (1981),Journal of Medicinal Chemistry, 1347, vol. 40, (1997), Journal ofMedicinal Chemistry, 5233, vol. 45, (2002), Organic Letters, 2856, vol.11, (2009), and the like]. Organic solvent includes aprotic solvent suchas N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide,and the like, ether type solvent such as tetrahydrofuran, 1,4-dioxane,and the like, halogenated hydrocarbons such as dichloromethane,chloroform, 1,2-dichloroethane, chlorobenzene, and the like,hydrocarbons such as toluene, benzene, and the like, mixed solventsthereof, and the like, and suitably N,N-dimethylformamide,N-methyl-2-pyrrolidone, dimethyl sulfoxide, acetonitrile, andtetrahydrofuran. In addition, it can be produced in a two-layer systemof organic solvent—water. Both of organic bases and inorganic bases canbe used as a base. Organic bases include 1-hydroxybenzotriazole,N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine,1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene,1,4-diazabicyclo[5.4.0]undec-7-ene, pyridine, dimethylaminopyridine,picoline, and the like. Inorganic bases include alkali halides such aspotassium fluoride and the like, alkali hydroxide such as sodiumhydroxide, potassium hydroxide, and the like, alkali carbonate such assodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate, and the like, alkali alkoxide such as sodium ethoxide, sodiumtert-butoxide, potassium tert-butoxide, and the like, alkali metal suchas n-butyl lithium, methyl lithium, isopropylmagnesium bromide, and thelike. The amount of compound (9-2) used is generally 1 to 5 mol,preferably, 1.2 to 3 mol per mol of compound (9-1). The amount of a baseused is generally 2 to 10 mol, preferably, 2 to 3 mol per mol ofcompound (1-1). A reaction time is generally about 0.5 to about 48hours, preferably, about 0.5 to about 12 hours. A reaction temperatureis generally about −20 to about 180° C., preferably, about 0 to about150° C.

Production Method 14:

[In the formulas, R², R³, R⁴, R⁵, R⁷, R⁸, L¹, L², A, and G are definedthe same as above.]

These steps (1 to 3) can produce compound (14-6) from compound (13-1) inaccordance with similar methods to methods and the like described inliterature [for example, US2012/0077986A1 and the like].

In each reaction of the production methods described above, in a caseother than the case where the use of a protecting group is specificallyand explicitly indicated, if any functional group other than a reactionpoint is modified under a described reaction condition or is unsuitablefor performing the described method, a target compound can be obtainedby protecting any point other than the reaction point as necessary, andunprotecting after the reaction is finished or a series of reactions areperformed.

As a protecting group, a common protecting group such as those describedin literature (e.g., Protective Groups in Organic Synthesis, 3^(rd) ed.,T. W. Greene, John Wiley & Sons Inc. (1999), and the like) can be used.Further specifically, examples of a protecting group for an amino groupcan include benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl, andthe like, and examples of a protecting group for a hydroxyl groupinclude trialkylsilyl groups such as trimethylsilyl,tert-butyldimethylsilyl, and the like, acetyl, benzyl, and the like,respectively.

Introduction and removal of a protecting group can be performed byroutine methods in synthetic organic chemistry (e.g., refer toProtective Groups in Organic Synthesis, described above) or methods inaccordance therewith.

In addition, intermediates or final products in the above-describedproduction methods can be derived to other compounds encompassed by thepresent invention by appropriately converting a functional groupthereof, and in particular, extend any kind of side chain using an aminogroup, a hydroxyl group, a carbonyl group, a halogen group, or the likeas an aid, and at this time, as necessary, performing theabove-described protection and deprotection. Conversion of a functionalgroup and extension of a side chain can be performed by a routine,general method (refer to, e.g., Comprehensive Organic Transformations,R. C. Larock, John Wiley & Sons Inc. (1999), and the like).

Intermediates and target compounds in the above-described respectiveproduction methods can be subjected to a routine purification method insynthetic organic chemistry, for example, neutralization, filtration,extraction, washing, drying, concentration, recrystallization, any kindof chromatography, and the like to isolate and purify it. In addition,the intermediates can be subjected to a next reaction without particularpurification.

Among starting materials and intermediates in respective productionmethods described above, those of which production methods are notparticularly and repeatedly described are commercially availablecompounds or can be synthesized from a commercially available compoundby a known method to those skilled in the art or a method in accordancetherewith.

The present compound is provided, for example, as an anticancer agent.Although the type of cancer to which it is applied is not limited,specific examples thereof include acute leukemia, chronic lymphocyticleukemia, chronic myelocytic leukemia, polycythemia vera, malignantlymphoma, brain tumor, head and neck cancer, esophageal cancer, thyroidcancer, small cell lung cancer, non-small-cell lung cancer, breastcancer, gastric cancer, gallbladder•bile duct cancer, hepatoma,pancreatic cancer, colon cancer, rectal cancer, chorioepithelioma,endometrial cancer, cervical cancer, urothelial cancer, renal cellcancer, testicular tumor, Wilms' tumor, skin cancer, malignant melanoma,neuroblastoma, osteosarcoma, Ewing's sarcoma, and soft tissue sarcoma.Hematological cancer in the present invention is a concept encompassinglymphoma and leukemia, and has an effect to reduce or annihilatecarcinoma or to inhibit the growth of carcinoma for the purposes ofpreventing/or treating cancer. It is noted that in the presentinvention, “prevention (preventing)” is an action to administer anactive ingredient of the present invention to a healthy human that doesnot develop a disease, and a purpose thereof is, for example, to preventthe onset of a disease. “Treatment (treating)” is an action toadminister an active ingredient of the present invention to a person(patient) diagnosed as developing a disease by a medical doctor, and apurpose thereof is, for example, to alleviate the disease and symptoms,to inhibit the growth of carcinoma, or to return it to a state prior tothe onset of the disease. In addition, even when the purpose ofadministration is to prevent a disease or symptoms from deteriorating orcarcinoma from growing, if it is administered to a patient, it is anaction for therapy.

When the present compound is administered, the amount of the compoundused varies depending on symptoms, age, administration method, and thelike. For example, in the case of oral administration, it is desirableto administer to an adult 0.01 mg as the lower limit (preferably 1 mg)and 5000 mg as the upper limit (preferably 500 mg) once or in severalbatches daily depending on the symptoms. In the case of intravenousinjection, an effect is expected by administering to an adult 0.01 mg asthe lower limit (preferably 0.1 mg) and 1000 mg as the upper limit(preferably 30 mg) once or in several batches daily depending on thesymptoms. Examples of its administration schedule include single-doseadministration, once a day administration for three days in a row, andthe like. Further, each administration described above can be repeatedat intervals of about 7 days to about 60 days.

The present compound can be administered orally or parenterally (e.g.,intravenous, subdermal, or intramuscular injection, ocularadministration, transrectally, percutaneously, transnasally, or thelike). For oral administration, for example, tablets, capsules, pills,granules, powders, solutions, suspensions, and the like can be used. Inaddition, for parenteral administration, injections, eye drops,suppositories, patches, poultices, lotions, creams, and the like can beused. These preparations comprise the present compound andpharmacologically acceptable additives, and produced using conventionalknown techniques.

More specifically, depending on parenteral or oral administration, thepresent compound can be formed into a preparation using a suitabledosage form, and administrated. Examples of the dosage form include, butare not limited to, tablets, capsules, powders, granules, solutions,suspensions, injections, patches, poultices, and the like. Thepreparation is produced by a known method using a pharmaceuticallyacceptable additive.

As additives, excipients, disintegrants, binders, fluidizers,lubricants, coating agents, solvents, solubilizing agents, thickeners,dispersants, stabilizers, sweeteners, flavors, and the like can be usedin accordance with a purpose. Specific examples thereof include lactose,mannitol, crystalline cellulose, low-substituted hydroxypropylcellulose,corn starch, partly pregelatinized starch, carmellose calcium,croscarmellose sodium, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, magnesium stearate, sodium stearylfumarate, polyethylene glycol, propylene glycol, titanium oxide, talc,and the like.

It is possible to more effectively perform preventive treatment ofcancer by combining one to three types selected from the groupconsisting of: (1) administering an effective amount of the presentcompound; and (2) (i) administering an effective amount of anotheranticancer agent, (ii) administering an effective amount of a hormonaltherapeutic agent; and (iii) non-pharmacological therapy. Examples ofnon-pharmacological therapy include surgery, radiotherapy, gene therapy,thermotherapy, cryotherapy, laser cauterization therapy, and the like.Two or more types of these also can be combined.

The present compound can be used in combination with another drug forpurpose of enhancing its effect. Specifically, the present compound canbe used in combination with a drug such as a hormonal therapeutic agent,a chemotherapeutic agent, an immunotherapeutic agent, or a cell growthfactor, a pharmaceutical agent to inhibit its receptor activity, and thelike. Hereinafter, a drug that may be used in combination with thepresent compound is abbreviated to a combination drug.

The present compound, even when used as a single agent, exhibitsexcellent anticancer effect, and further the combination use with one orseveral of the above-described combination drugs (polypharmacy) canfurther enhance its effect or improve the QOL of a patient.

Examples of “hormonal therapeutic agents” include Fosfestrol,Diethylstilbestrol, Chlorotrianisene, Medroxyprogesterone acetate,Megestrol acetate, Chlormadinone acetate, Cyproterone acetate, Danazol,Dienogest, Asoprisnil, Allylestrenol, Gestrinone, Nomegestrol, Tadenan,Mepartricin, Raloxifene, Ormeloxifene, Levormeloxifene, antiestrogen(e.g., Tamoxifen citrate, Toremifene citrate, and the like), pillpreparation, Mepitiostane, Testololactone, aminoglutethimide, LH-RHderivatives (LH-RH agonist (e.g., Goserelin acetate, Buserelin,Leuprorelin, and the like), LH-RH antagonist), Droloxifene,Epitiostanol, ethynyl estradiol sulfonate, aromatase inhibitor (e.g.,Fadrozole hydrochloride, Anastrozole, Letrozole, exemestane, vorozole,formestane, and the like), anti-androgen (e.g., Flutamide, Bicalutamide,Nilutamide, and the like), adrenocortical hormone type pharmaceuticalagent (e.g., Dexamethasone, Prednisolone, Betamethasone, Triamcinolone,and the like), androgen synthesis inhibitor (e.g., Abiraterone and thelike), retinoid and a pharmaceutical agent to delay the metabolism ofretinoid (e.g., Liarozole and the like), and the like.

As “chemotherapeutic agents”, for example, alkylating agents,antimetabolites, anticancer antibiotics, plant-derived anticanceragents, other chemotherapeutic agents, and the like are used.Representative examples are described below.

Examples of “alkylating agents” include Nitrogen mustard, Nitrogenmustard N-oxide hydrochloride, Chlorambucil, Cyclophosphamide,Ifosfamide, Thiotepa, Carboquone, Improsulfan tosylate, Busulfan,Nimustine hydrochloride, Mitobronitol, Melphalan, Dacarbazine,Ranimustine, Estramustine phosphate sodium, Triethylenemelamine,Carmustine, Lomustine, Streptozocin, Pipobroman, Etoglucide,Carboplatin, Cisplatin, miriplatin, Nedaplatin, Oxaliplatin,Altretamine, Ambamustine, Dibrospidium chloride, Fotemustine,Prednimustine, Pumitepa, Ribomustin, Temozolomide, Treosulfan,Trofosfamide, Zinostatin stimalamer, Adozelesin, Cystemustine,Bizelesin, and DDS preparations thereof, and the like.

Examples of “antimetabolites” include Mercaptopurine, 6-Mercaptopurineriboside, Thioinosine, Methotrexate, Pemetrexed, Enocitabine,Cytarabine, Cytarabin ocfosfate, Ancitabine hydrochloride, 5-FU typepharmaceutical agent (e.g., Fluorouracil, Tegafur, UFT, Doxifluridine,Carmofur, Galocitabine, Emitefur, Capecitabine, and the like),Aminopterin, Nelarabine, Leucovorin calcium, tabloid, Butocin, calciumfolinate, calcium levofolinate, Cladribine, Emitefur, Fludarabine,Gemcitabine, hydroxycarbamide, Pentostatin, Piritrexim, Idoxuridine,Mitoguazone, Tiazofurin, Ambamustine, Bendamustine, and DDS preparationsthereof, and the like.

Examples of “anticancer antibiotics” include Actinomycin D, ActinomycinC, Mitomycin C, Chromomycin A3, Bleomycin hydrochloride, Bleomycinsulfate, Peplomycin sulfate, Daunorubicin hydrochloride, Doxorubicinhydrochloride, Aclarubicin hydrochloride, Pirarubicin hydrochloride,Epirubicin hydrochloride, Neocarzinostatin, Mithramycin, Sarkomycin,Carzinophilin, Mitotane, Zorubicin hydrochloride, Mitoxantronehydrochloride, Idarubicin hydrochloride, and DDS preparations thereof,and the like.

Examples of “plant-derived anticancer agents” include Etoposide,Etoposide phosphate, Vinblastine sulfate, Vincristine sulfate, Vindesinesulfate, Teniposide, Paclitaxel, Docetaxel, DJ-927, Vinorelbine,Irinotecan, Topotecan, and DDS preparations thereof, and the like.

Examples of “other chemotherapeutic agents” include Sobuzoxane and thelike.

Examples of “immunotherapeutic agents (BRM)” include Picibanil, Krestin,Sizofiran, Lentinan, Ubenimex, interferon, interleukin, macrophagecolony stimulating factor, granulocyte-colony stimulating factor,Erythropoietin, Lymphotoxin, BCG vaccine, Corynebacterium parvum,Levamisole, polysaccharide K, Procodazole, anti-CTLA4 antibody, PD-1antibody, Toll-like Receptors agonist (e.g., TLR7 agonist, TLR8 agonist,TLR9 agonist, and the like).

A cell growth factor and a cell growth factor in a pharmaceutical agentto inhibit the activity of its receptor may be any substance as long asit promotes cell growth. Generally, they include a factor that is apeptide having a molecular weight of 20,000 or less and exhibits aneffect at a low concentration by binding with a receptor. Specifically,they include EGF (epidermal growth factor) or substances havingsubstantially the same activity as it (e.g., TGFalpha and the like),insulin or substances having substantially the same activity as it(e.g., insulin, IGF (insulin-like growth factor)-1, IGF-2, and thelike), FGF (fibroblast growth factor) or substances having substantiallythe same activity as it (e.g., acidic FGF, basic FGF, KGK (keratinocytegrowth factor), FGF-10, and the like), and other cell growth factors(e.g., CSF (colony stimulating factor), EPO (erythropoietin), IL-2(interleukin-2), NGF (nerve growth factor), PDGF (platelet-derivedgrowth factor), TGF-beta (transforming growth factor beta), HGF(hepatocyte growth factor), VEGF (vascular endothelial growth factor),heregulin, angiopoietin, and the like).

The period of administration of the present compound and a combinationpharmaceutical agent is not limited, and these may be administeredconcurrently or at intervals to a subject to be administered. Inaddition, a mixture of the present compound and a combinationpharmaceutical agent may be made. The dosage of a combinationpharmaceutical agent can be appropriately selected using clinically useddose as criteria. In addition, the mixing ratio of the present compoundand a combination pharmaceutical agent can be appropriately selecteddepending on a subject to be administered, an administration route,target disease, symptoms, combinations, and the like. For example, whena subject to be administered is a human, 0.01 to 100 parts by weight ofa combination pharmaceutical agent may be used relative to one part byweight of the present compound. In addition, for purpose of inhibitingits side effect, they can be used in combination with a pharmaceuticalagent (a combination pharmaceutical agent) such as an antiemetic agent,a sleep-inducing agent, an anticonvulsant, and the like.

EXAMPLES

Hereinafter, the present invention is more specifically described withreference examples, examples, and test examples. However, the scope ofthe present invention is certainly not limited to these examples. It isnoted that compound names shown in the following reference examples andexamples do not always follow the IUPAC nomenclature. It is noted thatalthough abbreviations are sometimes used to simplify a description,these abbreviations are defined the same as the above descriptions.

In the present specification, the following abbreviations are sometimesused.

In NMR and MS data of reference examples and examples, the followingabbreviations are used.

Me: a methyl groupEt: an ethyl groupNs: a 2-nitrobenzenesulfonyl groupTs: a p-toluenesulfonyl grouptert: tertiaryBoc: a tert-butoxycarbonyl group

DMF: N,N-dimethylformamide

DMSO: dimethyl sulfoxideHATU: O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphateHOBt: 1-hydroxybenzotriazole

NMP: N-methylpyrrolidone

THF: tetrahydrofuranWSC.HCl: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochlorides: singletbrs: broad singletd: doubletdd: double doublett: tripletq: quartetm: multipletbr: broadJ: coupling constant

Hz: Hertz

CDCl₃: deuterated chloroformDMSO-d₆: deuterated dimethyl sulfoxide

Analysis conditions for identification of a compound are as follow.

NMR: 400 MHz

MS: Kinetex, C18, 0.05% trifluoroacetic acid in water/0.05%trifluoroacetic acid in acetonitrile, acetonitrile 10-99% 3.0 min, 0.5mL/min, or BEH, C18, 0.05% formic acid in water/acetonitrile,acetonitrile 2-96% 2.2 min, 0.8 mL/min.

Reference Example 1 methyl 4,7-dimethoxy-1-benzothiophene-2-carboxylate

To a solution of 3,6-dimethoxy-2-nitrobenzaldehyde (70.0 g) in DMF (420mL) was added dropwise methyl mercaptoacetate (33.4 mL) at roomtemperature. Subsequently, potassium carbonate (137 g) was added theretoin 10 parts, and then at unchanged constant temperature the reactionmixture was stirred for 1 hour. Methyl iodide (41.3 mL) was addeddropwise thereto, followed by stirring for another 1 hour. The insolublesubstance was removed through Celite, and then solvent was evaporatedoff. The resulting residue was dissolved in ethyl acetate (700 mL),washed with water (2×700 mL) and saturated brine (700 mL), and thendried over sodium sulfate. The solvent was then evaporated off to yielda standard compound as a flesh-colored powder (81.1 g).

¹H-NMR (CDCl₃, δ ppm): 8.04 (1H, s), 7.04 (1H, d, J=8.4 Hz), 6.90 (1H,d, J=8.4 Hz), 3.92 (3H, s), 3.89 (3H, s), 3.88 (3H, s) MS (ESI+) 253(M⁺+1).

Reference Example 2 methyl5-amino-4,7-dimethoxy-1-benzothiophene-2-carboxylate (2A) ReferenceExample 3 methyl 6-amino-4,7-dimethoxy-1-benzothiophene-2-carboxylate(2B)

To a solution of methyl 4,7-dimethoxy-1-benzothiophene-2-carboxylate(2.04 g) (which was obtained in Reference example 1) in acetic acid (102mL) was added dropwise 70% aqueous nitric acid solution (512 μL), andthen the reaction mixture was stirred at 70° C. for 1 hour. After it wasreturned to room temperature, the reaction solution was poured into icedwater, and then extracted with chloroform two times. The resultingorganic layer was washed with saturated brine, and then dried oversodium sulfate. The solvent was then evaporated off to yield a mixtureof 1A and 1B (2.57 g). This was used in the next reaction withoutfurther purification.

To a suspension of 90% reduced iron (2.68 g) and ammonium chloride (555mg) in methanol/water (57.6 mL/28.8 mL), which had been heated andstirred at 75° C., was added dropwise a suspension of the obtainedmixture of 1A and 1B (2.57 g) in methanol (8.65 mL), and then thereaction mixture was stirred at 75° C. for 2 hours. After the reactionsolution was cooled to room temperature, it was filtered through Celite,and then the solvent of the resulting filtrate was evaporated off. Theresulting residue was dissolved in ethyl acetate, washed with aqueoussaturated sodium bicarbonate and saturated brine, and then dried oversodium sulfate. The solvent was evaporated off, and then the resultingresidue was purified by silica gel column chromatography (ethylacetate/hexane) to yield Compound 2A as a brown solid (1.74 g), andCompound 2B as a flesh-colored solid (474 mg).

(2A) ¹H-NMR (DMSO-d₆, δ ppm): 7.94 (1H, s), 6.69 (1H, s), 5.15 (2H, s),3.92 (3H, s), 3.91 (3H, s), 3.79 (3H, s).

MS (ESI+) 268 (M⁺+1).

(2B) ¹H-NMR (DMSO-d₆, δ ppm): 7.90 (1H, s), 6.46 (1H, s), 5.71 (2H, s),3.88 (3H, s), 3.87 (3H, s), 3.77 (3H, s).

MS (ESI+) 268 (M⁺+1).

Reference Example 4 methyl4,9-dimethoxythieno[2,3-g]quinoline-2-carboxylate (3B)

(a) 4,7-Dimethoxy-5-(prop-2-yn-1-ylamino)-1-benzothiophene-2-carboxylate(3A)

To a solution of methyl5-amino-4,7-dimethoxy-1-benzothiophene-2-carboxylate (274 mg) (which wasobtained in Reference example 2) in acetonitrile (3.1 mL) were addedpotassium carbonate (213 mg) and 3-bromopropyne (117 μL), and then thereaction mixture was heated and stirred at 70° C. for 6 hours. Thereaction solution was returned to room temperature, and then the solventwas evaporated off. The resulting residue was dissolved in ethylacetate, washed with water and saturated brine, and then dried oversodium sulfate. The solvent was evaporated off, and then the resultingresidue was purified by silica gel column chromatography (ethylacetate/hexane) to yield Compound 3A as a yellow solid (142 mg).

(b) Methyl 4,9-dimethoxythieno[2,3-g]quinoline-2-carboxylate (3B)

To a solution of Compound 3A (90.2 mg) (which was obtained above) inDMSO (6 mL) was added silver hexafluoroantimonate (10.2 mg), and thenthe reaction mixture was heated and stirred at 110° C. for 3 hours. Thereaction solution was returned to room temperature, ethyl acetate andwater were added thereto, followed by stirring for 5 minutes. Theresulting organic layer was washed with aqueous saturated sodiumbicarbonate and saturated brine, and then dried over sodium sulfate. Thesolvent was evaporated off, and then the resulting residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to yieldCompound 3B as a yellow solid (20.4 mg).

(3A) ¹H-NMR (CDCl₃, δ ppm): 8.04 (1H, s), 7.26 (1H, s), 6.54 (2H, s),4.49 (1H, brs), 4.05 (2H, s), 3.98 (3H, s), 3.94 (3H, s), 3.87 (3H, s),2.23 (1H, s).

MS (ESI+) 306 (M⁺+1).

(3B) ¹H-NMR (CDCl₃, δ ppm): 8.97 (1H, dd, J=1.6, 4.0 Hz), 8.55 (1H, dd,J=1.6, 8.8 Hz), 8.42 (1H, s), 7.46 (1H, dd, J=4.0, 8.8 Hz), 4.34 (3H,s), 4.16 (3H, s), 3.99 (3H, s).

MS (ESI+) 304 (M⁺+1).

Reference Example 5 4,9-dimethoxythieno[2,3-g]quinoline-2-carboxylicacid

To a solution of methyl4,9-dimethoxythieno[2,3-g]quinoline-2-carboxylate (70.0 mg) (which wasobtained in Reference example 4) in THF/ethanol (346 μL/346 μL) wasadded 1 N aqueous sodium hydroxide solution (692 μL), and then thereaction mixture was stirred at room temperature for 2 hours. After thesolvent was evaporated off, water was added thereto, and then the liquidproperty was made acidic (pH=2 to 3) with 2 N aqueous hydrochloric acidsolution. The reaction mixture was extracted with Ethyl acetate threetimes, and then the resulting organic layer was washed with saturatedbrine. The organic layer was dried over sodium sulfate, and then thesolvent was evaporated off to yield the title compound as a brown solid(65.2 mg).

¹H-NMR (DMSO-d₆, δ ppm): 8.99 (1H, dd, J=1.2, 4.4 Hz), 8.59 (1H, dd,J=1.2, 8.4 Hz), 8.20 (1H, s), 7.63 (1H, dd, J=4.4, 8.4 Hz), 4.27 (3H,s), 4.10 (3H, s).

MS (ESI+) 290 (M⁺+1).

Reference Example 6 1-(4,9-dimethoxythieno[2,3-g]quinolin-2-yl)ethanone(4B)

(a) (4,9-Dimethoxythieno[2,3-g]quinolin-2-yl) (morpholin-4-yl)methanone(4A)

To a solution of 4,9-dimethoxythieno[2,3-g]quinoline-2-carboxylic acid(35.2 mg) (which was obtained in Reference example 5) in DMF (1.2 mL)were added morpholine (21.2 μL), HATU (92.6 mg), and Hunig's base (128μL), and then the reaction mixture was stirred at room temperature for1.5 hours. The reaction solution was poured into water, and thenextracted with ethyl acetate three times. The resulting organic layerwas washed with saturated brine, and then dried over sodium sulfate. Thesolvent was then evaporated off to yield Compound 4A as a yellow solid(41.0 mg).

(b) 1-(4,9-Dimethoxythieno[2,3-g]quinolin-2-yl)ethanone (4B)

To a solution of Compound 4A (which was obtained above) in THF (1.14mL), under ice-cooling, was added dropwise methylmagnesium bromide (114μL), and then the reaction mixture was stirred at room temperature for3.5 hours. The reaction solution was poured into water, and thenextracted with ethyl acetate two times. The resulting organic layer waswashed with saturated brine, and then dried over sodium sulfate. Thesolvent was then evaporated off to yield Compound 4B as a brown solid(36.0 mg).

(4A) MS (ESI+) 359 (M⁺+1).

(4B) ¹H-NMR (CDCl₃, δ ppm): 8.97 (1H, dd, J=1.6, 4.0 Hz), 8.56 (1H, dd,J=1.6, 8.8 Hz), 8.30 (1H, s), 7.47 (1H, dd, J=4.0, 8.8 Hz), 4.39 (3H,s), 4.16 (3H, s), 2.74 (3H, s).

MS (ESI+) 288 (M⁺+1).

Example 1 2-acetylthieno[2,3-g]quinoline-4,9-dione

To a mixture solution of1-(4,9-dimethoxythieno[2,3-g]quinolin-2-yl)ethanone (4.0 mg) (which wasobtained in Reference example 6) in acetonitrile (1 mL) and water (1 mL)was added Ammonium Cerium Nitrate (16 mg) at 0° C., and then thereaction mixture was stirred for 1 hour. Aqueous saturated sodiumhydrogen carbonate solution was added to the reaction solution, whichwas then extracted with ethyl acetate. The organic layer was dried overanhydrous sodium sulfate, filtered, and then concentrated under reducedpressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate) to yield the title compound as a yellow solid(1.8 mg).

MS (ESI+) 258 (M⁺+1).

Example 2 2-(1-hydroxyethyl)thieno[2,3-g]quinoline-4,9-dione (5B)

(a) 1-(4,9-dimethoxythieno[2,3-g]quinolin-2-yl)ethanol (5A)

To a solution of 1-(4,9-dimethoxythieno[2,3-g]quinolin-2-yl)ethanone(34.9 mg) (which was obtained in Reference example 6) in THF (1.2 mL),under ice-cooling, was added sodium borohydride (10.0 mg), and then thereaction mixture was stirred at room temperature for 2 hours. Aqueoussaturated ammonium chloride solution was added thereto, and thenextraction with ethyl acetate was performed two times. The resultingorganic layer was washed with saturated brine, and then dried oversodium sulfate. The solvent was then evaporated off to yield Compound 5Aas a brown solid (33.3 mg).

(b) 2-(1-Hydroxyethyl)thieno[2,3-g]quinoline-4,9-dione (5B)

Using Compound 5A (32.1 mg) obtained above and according to the samemethod as Example 1, Compound 5B was obtained as a yellow solid (10.4mg).

(5A) ¹H-NMR (CDCl₃, δ ppm): 8.95 (1H, dd, J=2.0, 3.6 Hz), 8.53 (1H, dd,J=2.0, 8.8 Hz), 7.53 (1H, s), 7.41 (1H, dd, J=3.6, 8.8 Hz), 5.29-5.21(1H, m), 4.26 (3H, s), 4.14 (3H, s), 1.72 (3H, d, J=6.0 Hz).

MS (ESI+) 290 (M⁺+1).

(5B) ¹H-NMR (DMSO-d₆, δ ppm): 9.02 (1H, dd, J=2.0, 4.4 Hz), 8.47 (1H,dd, J=2.0, 8.0 Hz), 7.85 (1H, dd, J=4.4, 8.0 Hz), 7.57 (1H, s), 6.14(1H, d, J=5.2 Hz), 5.18-4.98 (1H, m), 1.50 (3H, d, J=6.0 Hz).

MS (ESI+) 260 (M⁺+1).

Example 3N,N-dimethyl-4,9-dioxo-4,9-dihydrothieno[2,3-g]quinoline-2-carboxamide(6B)

(a) 4,9-Dimethoxy-N,N-dimethylthieno[2,3-g]quinoline-2-carboxamide (6A)

To a solution of 4,9-dimethoxythieno[2,3-g]quinoline-2-carboxylic acid(25.9 mg) (which was obtained in Reference example 5) in DMF (1.0 mL)were added dimethylamine hydrochloride (8.8 mg), WSC.HCl (25.8 mg), HOBt(18.2 mg), and Hunig's base (57.9 μL), and then the reaction mixture wasstirred at room temperature for 1.5 hours. The reaction solution waspoured into water, and then extracted with ethyl acetate two times. Theresulting organic layer was washed with saturated brine, and then driedover sodium sulfate. The solvent was then evaporated off to yieldCompound 6A as a yellow solid (17.3 mg).

(b)N,N-dimethyl-4,9-dioxo-4,9-dihydrothieno[2,3-g]quinoline-2-carboxamide(6B)

Using Compound 6A (17.3 mg) obtained above and according to the samemethod as Example 1, the title compound 6B was obtained as a pale greensolid (5.5 mg).

(6A) MS (ESI+) 317 (M⁺+1).

(6B) MS (ESI+) 287 (M⁺+1).

Reference Example 7 2-(chloromethyl)-4,9-dimethoxythieno[2,3-g]quinoline(7A)

(a) (4,9-Dimethoxythieno[2,3-g]quinolin-2-yl)methanol (7A)

To a solution of methyl4,9-dimethoxythieno[2,3-g]quinoline-2-carboxylate (27.8 mg) (which wasobtained in Reference example 4) in dichloromethane (1.0 mL), underice-cooling, was added lithium aluminum hydride (73.6 mg), and then thereaction mixture was stirred at room temperature overnight. Underice-cooling, aqueous saturated Rochelle salt solution was added thereto,and then extraction with ethyl acetate was performed two times. Theresulting organic layer was washed with saturated brine, and then driedover sodium sulfate. The solvent was then evaporated off to yieldCompound 7A as a yellow oil (22.7 mg).

(b) 2-(Chloromethyl)-4,9-dimethoxythieno[2,3-g]quinoline (7B)

To a solution of Compound 7A (22.7 mg) (which was obtained above) indichloromethane (1.0 mL), under ice-cooling, was added thionyl chloride(7.6 μL), and then the reaction mixture was stirred at room temperaturefor 2 hours. The solvent was evaporated off, and then azeotropy of theresulting residue with toluene yields Compound 7B as a brown oil (23.7mg).

(7A) MS (ESI+) 276 (M⁺+1).

(7B) MS (ESI+) 294 (M⁺+1).

Reference Example 84,9-dimethoxy-2-(morpholin-4-ylmethyl)thieno[2,3-g]quinoline

To a solution of 2-(chloromethyl)-4,9-dimethoxythieno[2,3-g]quinoline(which was obtained in Reference example 7) in acetonitrile (1.0 mL)were added Hunig's base (28.8 μL), morpholine (7.9 μL), and sodiumiodide (a catalytic amount), and then the reaction mixture was stirredat room temperature overnight. The solvent was evaporated off, and thenthe resulting residue was purified by silica gel column chromatography(ethyl acetate/hexane→chloroform/methanol) to yield the title compoundas a yellow solid (19.1 mg).

MS (ESI+) 345 (M⁺+1).

Example 4 2-(morpholin-4-ylmethyl)thieno[2,3-g]quinoline-4,9-dione

Using 4,9-dimethoxy-2-(morpholin-4-ylmethyl)thieno[2,3-g]quinoline (19.1mg) obtained in Reference example 8 and according to the same method asExample 1, the title compound was obtained as a pale green solid (13.3mg).

MS (ESI+) 315 (M⁺+1).

Example 52-{[cyclohexyl(ethyl)amino]methyl}thieno[2,3-g]quinoline-4,9-dione (8B)

(a)N-[(4,9-dimethoxythieno[2,3-g]quinolin-2-yl)methyl]-N-ethylcyclohexaneamine(8A)

Using cyclohexylethylamine (16.8 μL) and according to the same method asReference example 8, Compound 8A was obtained as a yellow oil (13.5 mg).

(b) 2-{[Cyclohexyl(ethyl)amino]methyl}thieno[2,3-g]quinoline-4,9-dione(8B)

Using Compound 8A (13.5 mg) obtained above and according to the samemethod as Example 1, the title compound 8B was obtained as a brown solid(7.9 mg).

(8A) MS (ESI+) 385 (M⁺+1).

(8B) MS (ESI+) 355 (M⁺+1).

Example 62-{[ethyl(2-methoxyethyl)amino]methyl}thieno[2,3-g]quinoline-4,9-dione(9B)

(a)N-[(4,9-dimethoxythieno[2,3-g]quinolin-2-yl)methyl]-N-ethyl-2-methoxyethaneamine(9A)

Using 2-methoxyethylethylamine (14.9 μL) and according to the samemethod as Reference example 8, Compound 9A was obtained as a yellow oil(13.3 mg).

(b)2-{[Ethyl(2-methoxyethyl)amino]methyl}thieno[2,3-g]quinoline-4,9-dione(9B)

Using Compound 9A (13.3 mg) obtained above and according to the samemethod as Example 1, the title compound 9B was obtained as a brown solid(11.5 mg).

(9A) MS (ESI+) 361 (M⁺+1).

(9B) MS (ESI+) 331 (M⁺+1).

Example 72-{[ethyl(pyridin-4-ylmethyl)amino]methyl}thieno[2,3-g]quinoline-4,9-dione(10B)

(a)N-[(4,9-dimethoxythieno[2,3-g]quinolin-2-yl)methyl]-N-(pyridin-4-ylmethyl)ethanamine(10A)

Using N-ethyl-4-picolylamine (26.4 mg) and according to the same methodas Reference example 8, Compound 10A was obtained as a brown solid (18.0mg).

(b)2-{[Ethyl(pyridin-4-ylmethyl)amino]methyl}thieno[2,3-g]quinoline-4,9-dione(10B)

Using Compound 10A (18.0 mg) obtained above and according to the samemethod as Example 1, the title compound 10B was obtained as a brownsolid (10.3 mg).

(10A) MS (ESI+) 394 (M⁺+1).

(10B) MS (ESI+) 364 (M⁺+1).

Example 82-{[ethyl(pyridin-4-ylmethyl)amino]methyl}thieno[2,3-g]quinoline-4,9-dione(11B)

(a)N′2′-[(4,9-dimethoxythieno[2,3-g]quinolin-2-yl)methyl]-N′2′-ethyl-N,N-dimethylglycinamide(11A)

Using 2-ethylamino-N,N-dimethylacetamide (25.2 mg) and according to thesame method as Reference example 8, Compound 11A was obtained as a brownsolid (28.0 mg).

(b)2-{[Ethyl(pyridin-4-ylmethyl)amino]methyl}thieno[2,3-g]quinoline-4,9-dione(11B)

Using Compound 11A (28.0 mg) obtained above and according to the samemethod as Example 1, the title compound 11B was obtained as a brown oil(16.0 mg).

(11A) MS (ESI+) 388 (M⁺+1).

(11B) MS (ESI+) 358 (M⁺+1).

Reference Example 9N-[(4,9-dimethoxyfuro[2,3-g]quinolin-2-yl)methyl]ethanamine

Using ethylamine and according to the same method as

Reference example 8, the title compound was obtained as a brown oil (127mg).

MS (ESI+) 303 (M⁺+1).

Example 9N-[(4,9-dioxo-4,9-dihydrofuro[2,3-g]quinolin-2-yl)methyl]-N-ethyl-3-methylbutanamide(12B)

(a)N-[(4,9-dimethoxyfuro[2,3-g]quinolin-2-yl)methyl]-N-ethyl-3-methylbutanamide(12A)

To a solution ofN-[(4,9-dimethoxyfuro[2,3-g]quinolin-2-yl)methyl]ethaneamine (40.0 mg)(which was obtained in Reference example 9) in THF (1 mL), underice-cooling, were added dropwise isovaleyl chloride (19.4 μL) andtriethylamine (27.7 μL), and then the reaction mixture was stirred atroom temperature for 1 hour. Aqueous saturated sodium bicarbonate wasadded thereto, and then extraction with ethyl acetate was performed. Theresulting organic layer was washed with saturated brine, and then driedover sodium sulfate. The solvent was then evaporated off. The resultingresidue was purified by silica gel column chromatography (ethylacetate/hexane) to yield Compound 12A as a yellow solid (26.1 mg).

(b)N-[(4,9-dioxo-4,9-dihydrofuro[2,3-g]quinolin-2-yl)methyl]-N-ethyl-3-methylbutanamide(12B)

Using Compound 12A (28.0 mg) obtained above and according to the samemethod as Example 1, the title compound 12B was obtained as a yellowpowder (17.7 mg).

(12A) MS (ESI+) 387 (M⁺+1).

(12B) ¹H-NMR (DMSO-d₆, δ ppm): 9.02 (1H, d, J=2.8 Hz), 8.46 (1H, dd,J=1.6, 8.0 Hz), 7.84 (1H, dd, J=4.4, 8.0 Hz), 7.70-7.64 (1H, m),4.92-4.75 (2H, m), 3.48-3.36 (2H, m), 2.26 (2H, d, J=6.8 Hz), 2.15-2.02(1H, m), 1.17-1.01 (3H, m), 0.96-0.84 (6H, m).

MS (ESI+) 357 (M⁺+1).

Example 10N-[(4,9-dioxo-4,9-dihydrofuro[2,3-g]quinolin-2-yl)methyl]-N-ethyl-2-methylpropane-1-sulfonamide(13B)

(a)N-[(4,9-dimethoxyfuro[2,3-g]quinolin-2-yl)methyl]-N-ethyl-2-methylpropane-1-sulfonamide(13A)

Using N-[(4,9-dimethoxyfuro[2,3-g]quinolin-2-yl)methyl]ethaneamine (40.0mg) (which was obtained in Reference example 9) and isobutanesulfonylchloride (20.7 μL) and according to the same method as Example 9a,Compound 13A was obtained as a yellow solid (21.2 mg).

(b)N-[(4,9-dioxo-4,9-dihydrofuro[2,3-g]quinolin-2-yl)methyl]-N-ethyl-2-methylpropane-1-sulfonamide(13B)

Using Compound 13A (20.5 mg) obtained above and according to the samemethod as Example 1, the title compound 13B was obtained as a yellowpowder (16.8 mg).

(13A) MS (ESI+) 423 (M⁺+1).

(13B) ¹H-NMR (DMSO-d₆, δ ppm): 9.03 (1H, dd, J=2.0, 4.4 Hz), 8.48 (1H,dd, J=2.0, 8.0 Hz), 7.86 (1H, dd, J=4.8, 8.0 Hz), 7.70-7.64 (1H, m),4.72-4.65 (2H, m), 3.36-3.22 (2H, m), 3.08 (2H, d, J=6.4 Hz), 2.19-2.08(1H, m), 1.15-1.08 (3H, m), 1.08-1.02 (6H, m).

MS (ESI+) 393 (M⁺+1).

Example 11 ethyl[(4,9-dioxo-4,9-dihydrofuro[2,3-g]quinolin-2-yl)methyl]ethylcarbamate(14B)

(a) Ethyl [(4,9-dimethoxyfuro[2,3-g]quinolin-2-yl)methyl]ethylcarbamate(14A)

Using N-[(4,9-dimethoxyfuro[2,3-g]quinolin-2-yl)methyl]ethaneamine (40.0mg) (which was obtained in Reference example 9) and ethyl chloroformate(15.1 μL) and according to the same method as Example 9a, Compound 14Awas obtained as a yellow solid (21.9 mg).

(b) Ethyl[(4,9-dioxo-4,9-dihydrofuro[2,3-g]quinolin-2-yl)methyl]ethylcarbamate(14B)

Using Compound 14A (21.5 mg) obtained above and according to the samemethod as Example 1, the title compound 14B was obtained as a yellowpowder (16.2 mg).

(14A) MS (ESI+) 375 (M⁺+1).

(14B) ¹H-NMR (DMSO-d₆, δ ppm): 9.03 (1H, d, J=4.8 Hz), 8.47 (1H, d,J=7.2 Hz), 7.89-7.82 (1H, m), 7.69 (1H, s), 4.72 (2H, s), 4.13 (2H, q,J=6.8), 3.32 (2H, q, J=6.8 Hz), 1.22 (3H, t, J=6.8 Hz), 1.08 (3H, t,J=6.8 Hz).

MS (ESI+) 345 (M⁺+1).

Reference Example 10 4,9-dimethoxythieno[2,3-g]isoquinoline-2-carboxylicacid (15D)

(a) Methyl 5-formyl-4,7-dimethoxy-1-benzothiophene-2-carboxylate (15A)

Under nitrogen atmosphere, to a solution of methyl4,7-dimethoxy-1-benzothiophene-2-carboxylate (10 g) (which was obtainedin Reference example 1) in dichloromethane (250 mL) was added dropwisetitanium tetrachloride (9.9 mL) at 0° C., and then the reaction mixturewas stirred for 30 minutes. 1,1-Dichloromethyl methyl ether (4.6 mL) wasadded dropwise thereto, and then the reaction mixture was stirred at 0°C. for 2 hours followed by at room temperature for 1 hour. The reactionsolution was poured into iced water, and then extracted with chloroform.The organic layer was dried over anhydrous sodium sulfate, filtered, andthen concentrated under reduced pressure. The resulting residue wasrecrystallized from ethyl acetate to yield Compound 15A (10.2 g).

(b) Methyl5-{[(2,2-dimethoxyethyl)amino]methyl}-4,7-dimethoxy-1-benzothiophene-2-carboxylate(15B)

A solution of Compound 15A (31.8 g) (which was obtained above),aminoacetaldehyde dimethyl acetal (25 mL), and trimethyl orthoformate (5mL) in toluene (500 mL) was heated at reflux for 2 hours usingDean-Stark apparatus. The residue resulting from the concentration ofthe reaction solution under reduced pressure was dissolved in methanol(300 mL), and then sodium borohydride (4.3 g) was added at 0° C.thereto, followed by stirring for 30 minutes. Water (300 mL) was addedto the residue resulting from the concentration of the reaction solutionunder reduced pressure, and then extraction with ethyl acetate wasperformed. The organic layer was dried over anhydrous sodium sulfate,filtered, and then concentrated under reduced pressure. The resultingresidue was recrystallized at −78° C. using a mixed solvent of diethylether and hexane to yield Compound 15B (32.6 g).

(c) Methyl5-({(2,2-dimethoxyethyl)[(2-nitrophenyl)sulfonyl]amino}methyl)-4,7-dimethoxy-1-benzothiophene-2-carboxylate(15C)

To a solution of Compound 15B (25 g) (which was obtained above) inchloroform (300 mL) was added aqueous saturated sodium hydrogencarbonate solution (200 mL) and 2-nitrobenzenesulfonyl chloride (15 g),and then the reaction mixture was stirred at room temperature for 4hours. The reaction solution was extracted with chloroform. The organiclayer was dried over anhydrous sodium sulfate, filtered, and thenconcentrated under reduced pressure. The resulting residue wasrecrystallized from diethyl ether to yield Compound 15C (35.6 g).

(d) 4,9-Dimethoxythieno[2,3-g]isoquinoline-2-carboxylic acid (15D)

To a solution of Compound 15C (1 g) (which was obtained above) in1,4-dioxane (10 mL) was added 35% hydrochloric acid (10 mL), and thenthe reaction mixture was heated at reflux for 5 hours. The reactionsolution was poured into iced water, and then the precipitated solid wascollected by filtration and dried. The resulting residue was dissolvedin methanol (10 mL), and then activated carbon (200 mg) was addedthereto. After stirring for 30 minutes, it was filtered, and thenconcentrated under reduced pressure. The resulting residue was washedwith ethyl acetate, and then collected by filtration to yield Compound15D (330 mg).

(15A) ¹H-NMR (DMSO-d₆, δ ppm): 10.36 (1H, s), 8.27 (1H, s), 7.22 (1H,s), 4.09 (3H, s), 3.99 (3H, s), 3.91 (3H, s).

MS (ESI+) 281 (M⁺+1).

(15B) ¹H-NMR (DMSO-d₆, δ ppm): 8.06 (1H, s), 7.17 (1H, s), 4.41 (1H, t,J=5.2 Hz), 3.93 (3H, s), 3.88 (3H, s), 3.85 (3H, s), 3.81 (2H, s), 2.59(2H, d, J=5.5 Hz).

MS (ESI+) 370 (M⁺+1).

(15C) ¹H-NMR (DMSO-d₆, δ ppm): 8.10 (1H, s), 8.05 (1H, d, J=7.3 Hz),7.99 (1H, d, J=7.3 Hz), 7.85 (1H, t, J=7.6 Hz), 7.75 (1H, t, J=7.6 Hz),6.75 (1H, s), 4.73 (2H, s), 4.38 (1H, t, J=5.2 Hz), 3.89 (3H, s), 3.87(3H, s), 3.75 (3H, s), 3.39-3.34 (2H, m), 3.16 (6H, s).

MS (ESI+) 555 (M⁺+1).

(15D) ¹H-NMR (DMSO-d₆, δ ppm): 9.85 (1H, s), 8.57 (1H, d, J=6.7 Hz),8.45 (1H, s), 8.27 (1H, d, J=6.7 Hz), 4.35 (3H, s), 4.11 (3H, s).

MS (ESI+) 290 (M⁺+1).

Reference Example 111-(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)ethanone (16B)

(a) (4,9-Dimethoxythieno[2,3-g]isoquinolin-2-yl)(morpholin-4-yl)methanone (16A)

Using 4,9-dimethoxythieno[2,3-g]isoquinoline-2-carboxylic acid (286.0mg) obtained in Reference example 10 and according to the same method asReference example 6a, the title compound 16A was obtained as a yellowpowder (132 mg).

(b) 1-(4,9-Dimethoxythieno[2,3-g]isoquinolin-2-yl)ethanone (16B)

Using Compound 16A (132.0 mg) obtained above and according to the samemethod as Reference example 6b, the title compound 16B was obtained as ayellow powder (46 mg).

(16A) MS (ESI+) 359 (M⁺+1).

(16B) MS (ESI+) 288 (M⁺+1).

Example 12 2-acetylthieno[2,3-g]isoquinoline-4,9-dione

Using 1-(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)ethanone (46.0 mg)obtained in Reference example 11 and according to the same method asExample 1, the title compound was obtained as a yellow powder (19 mg).

MS (ESI+) 258 (M⁺+1).

Example 13 2-(1-hydroxyethyl)thieno[2,3-g]isoquinoline-4,9-dione (17B)

(a) 1-(4,9-Dimethoxythieno[2,3-g]isoquinolin-2-yl)ethanol (17A)

Using 1-(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)ethanone (52.0 mg)obtained in Reference example 11 and according to the same method asExample 2a, Compound 17A was obtained as a yellow powder (44.0 mg).

(b) 2-(1-Hydroxyethyl)thieno[2,3-g]isoquinoline-4,9-dione (17B)

Using Compound 17A (44.0 mg) obtained above and according to the samemethod as Example 1, the title compound 17B was obtained as a yellowpowder (29.0 mg).

(17A) MS (ESI+) 290 (M⁺+1).

(17B) MS (ESI+) 260 (M⁺+1).

Reference Example 12(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)methanol

To a solution of 4,9-dimethoxythieno[2,3-g]isoquinoline-2-carboxylicacid (100 mg) (which was obtained in Reference example 10) andN-methylmorpholine (411 μL) in dimethoxyethane (5.0 mL), underice-cooling, was added isobutyl chloroformate (270 μL), and then thereaction mixture was stirred for 20 minutes. After Celite filtration,under ice-cooling, an aqueous solution of sodium borohydride (257 mg)was added to the filtrate. After stirring for 2 hours, 2.0 mol/L aqueoussodium hydroxide solution was added thereto, and then the mixture wasstirred for 24 hours. After the reaction solution was extracted withethyl acetate, the resulting organic layer was washed with water andsaturated brine, and then dried over sodium sulfate. The solvent wasthen evaporated off. The resulting residue was purified by silica gelcolumn chromatography (chloroform/methanol) to yield the title compound(41 mg).

MS (ESI+) 276 (M⁺+1).

Example 14 2-(1-hydroxymethyl)thieno[2,3-g]isoquinoline-4,9-dione

Using (4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)methanol (20 mg)obtained in Reference example 12 and according to the same method asExample 1, the title compound was obtained as a yellow powder (9.0 mg).

MS (ESI+) 246 (M⁺+1).

Example 15 2-(2-hydroxypropan-2-yl)thieno[2,3-g]isoquinoline-4,9-dione(18B)

(a) 2-(4,9-Dimethoxythieno[2,3-g]isoquinolin-2-yl)propan-2-ol (18A)

To a solution of 1-(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)ethanone(33 mg) (which was obtained in Reference example 11) in THF (1.0 mL),under ice-cooling, was added dropwise 3 N methylmagnesium bromide (1.0mL), and then the reaction mixture was stirred for 1 hour. Methanol wasadded to the reaction solution, and then aqueous saturated ammoniumchloride solution was added. After extraction with ethyl acetate twotimes, the resulting organic layer was washed with water and saturatedbrine, and then dried over sodium sulfate. The solvent was thenevaporated off. The resulting residue was purified by silica gel columnchromatography (chloroform/methanol) to yield Compound 18A (23 mg).

(b) 2-(2-Hydroxypropan-2-yl)thieno[2,3-g]isoquinoline-4,9-dione (18B)

Using Compound 18A (23 mg) obtained above and according to the samemethod as Example 1, the title compound 18B was obtained as a yellowpowder (9.0 mg).

(18A) MS (ESI+) 304 (M⁺+1).

(18B) MS (ESI+) 274 (M⁺+1).

Reference Example 132-[cyclopropyl(ethoxy)methyl]-4,9-dimethoxythieno[2,3-g]isoquinoline(19C)

(a) Cyclopropyl(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)methanone(19A)

Using (4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)(morpholin-4-yl)methanone (100 mg) (which was obtained in Referenceexample 11a) and cyclopropylmagnesium bromide (1.95 mL) and according tothe same method as Reference example 6b, Compound 19A was obtained (23mg).

(b) Cyclopropyl(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)methanol(19B)

Using Compound 19A (52 mg) obtained above and according to the samemethod as Example 2a, Compound 19B was obtained (17 mg).

(c) 2-[Cyclopropyl(ethoxy)methyl]-4,9-dimethoxythieno[2,3-g]isoquinoline(19C)

To a solution of Compound 19B (28 mg) (which was obtained above) in THF(1.0 mL), under ice-cooling, was added sodium hydride (6.0 mg), and thenthe reaction mixture was stirred for minutes. Subsequently, ethyl iodide(28 μL) was added dropwise. After that, dimethylformamide (1.0 mL) wasadded, and then the reaction mixture was stirred at room temperature for1 hour. Water was added, and then extracted with ethyl acetate. Theresulting organic layer was washed with saturated brine, and then driedover sodium sulfate. The solvent was then evaporated off. The resultingresidue was purified by silica gel column chromatography (hexane/ethylacetate) to yield the title compound 19C (8.0 mg).

(19A) MS (ESI+) 314 (M⁺+1).

(19B) MS (ESI+) 316 (M⁺+1).

(19C) MS (ESI+) 344 (M⁺+1).

Example 162-[cyclopropyl(hydroxy)methyl]thieno[2,3-g]isoquinoline-4,9-dione

Using cyclopropyl(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)methanol(17 mg) obtained in Reference example 13b and according to the samemethod as Example 1, the title compound was obtained as a yellow powder(9.0 mg).

MS (ESI+) 286 (M⁺+1).

Example 172-[cyclopropyl(ethoxy)methyl]thieno[2,3-g]isoquinoline-4,9-dione

Using2-[cyclopropyl(ethoxy)methyl]-4,9-dimethoxythieno[2,3-g]isoquinoline(8.0 mg) obtained in Reference example 13c and according to the samemethod as Example 1, the title compound was obtained as a yellow powder(9.0 mg).

MS (ESI+) 314 (M⁺+1).

Example 18 2-[(benzyloxy)methyl]thieno[2,3-g]isoquinoline-4,9-dione(20B)

(a) 2-[(Benzyloxy)methyl]-4,9-dimethoxythieno[2,3-g]isoquinoline (20A)

To a solution of (4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)methanol(20 mg) (which was obtained in Reference example 12), phenol (10 mg),and triphenylphosphine (29 mg) in toluene (2 mL) was added dropwisediisopropyl azodicarboxylate (22 μL), and then the reaction mixture wasstirred at room temperature for 2 hours. The reaction solution waspurified by silica gel column chromatography (hexane:ethyl acetate=100:0to 0:100) to yield a mixture comprising Compound 20A.

(b) 2-[(Benzyloxy)methyl]thieno[2,3-g]isoquinoline-4,9-dione (20B)

Using a mixture comprising 20A obtained above and according to the samemethod as Example 1, the title compound 20B (1.8 mg) was obtained.

(20A) MS (ESI+) 352 (M⁺+1).

(20B) ¹H-NMR (DMSO-d₆, δ ppm): 9.36 (1H, br s), 9.20 (1H, br s), 8.03(1H, br s), 7.88 (1H, s), 7.40 (2H, t, J=7.9 Hz), 7.15 (2H, d, J=7.9Hz), 7.06 (1H, t, J=7.3 Hz), 5.59 (2H, br s).

MS (ESI+) 323 (M⁺+1).

Reference Example 14 methyl4,9-dioxo-4,9-dihydrothieno[2,3-g]isoquinoline-2-carboxylate (21B)

(a) Methyl 4,9-dimethoxythieno[2,3-g]isoquinoline-2-carboxylate (21A)

To a solution of 4,9-dimethoxythieno[2,3-g]isoquinoline-2-carboxylicacid (55.0 mg) (which was obtained in Reference example 10) in DMF (10mL) were added potassium carbonate (50 g) and methyl iodide (10 μL) atroom temperature, and then the reaction mixture was stirred for 1 hour.The insoluble was removed by Celite, and then the solvent was evaporatedoff. The resulting residue was purified by silica gel columnchromatography (chloroform/ethyl acetate) to yield Compound 21A (52 mg).

(b) Methyl 4,9-dioxo-4,9-dihydrothieno[2,3-g]isoquinoline-2-carboxylate(21B)

Using Compound 21A (52 mg) obtained above and according to the samemethod as Example 1, the title compound 21B was obtained as a yellowpowder (29 mg).

(21A) MS (ESI+) 304 (M⁺+1).

(21B) MS (ESI+) 274 (M⁺+1).

Example 19N,N-dimethyl-4,9-dioxo-4,9-dihydrothieno[2,3-g]isoquinoline-2-carboxyamide(22B)

(a) 4,9-Dimethoxy-N,N-dimethylthieno[2,3-g]isoquinoline-2-carboxyamide(22A)

Using 4,9-dimethoxythieno[2,3-g]isoquinoline-2-carboxylic acid (99.0 mg)(which was obtained in Reference example 10) and dimethylaminehydrochloride and according to the same method as Reference example 6a,Compound 22A was obtained as a yellow solid (46 mg).

(b)N,N-dimethyl-4,9-dioxo-4,9-dihydrothieno[2,3-g]isoquinoline-2-carboxamide(22B)

Using Compound 22A (46.0 mg) obtained above and according to the samemethod as Example 1, the title compound 22B was obtained as a paleyellow solid (18.0 mg).

(22A) MS (ESI+) 317 (M⁺+1).

(22B) MS (ESI+) 287 (M⁺+1).

Example 20 2-(morpholin-4-ylcarbonyl)thieno[2,3-g]isoquinoline-4,9-dione

Using Compound 16A (50 mg) obtained in Reference example 11a andaccording to the same method as Example 1, the title compound wasobtained as a pale yellow solid (18.0 mg).

MS (ESI+) 329 (M⁺+1).

Example 21N-(2,2-difluoroethyl)-4,9-dioxo-4,9-dihydrothieno[2,3-g]isoquinoline-2-carboxyamide(23B)

(a)N-(2,2-difluoroethyl)-4,9-dimethoxythieno[2,3-g]isoquinoline-2-carboxyamide(23A)

Using 4,9-dimethoxythieno[2,3-g]isoquinoline-2-carboxylic acid (30 mg)(which was obtained in Reference example 10) and 2,2-difluoroethylamine(20 μL) and according to the same method as Reference example 6a,Compound 23A was obtained.

(b)N-(2,2-difluoroethyl)-4,9-dioxo-4,9-dihydrothieno[2,3-g]isoquinoline-2-carboxyamide(23B)

Using Compound 23A obtained above and according to the same method asExample 1, the title compound 23B was obtained as a pale yellow solid(6.1 mg).

(23A) MS (ESI+) 353 (M⁺+1).

(23B) MS (ESI+) 323 (M⁺+1).

Example 22 3-(morpholin-4-ylcarbonyl)thieno[2,3-g]isoquinoline-4,9-dione(24G)

(a) Methyl 4,7-dimethoxy-1-benzothiophene-3-carboxylate (24A)

A solution of 2,5-dimethoxythiophenol (1 g), azobisisobutyronitrile (19mg), and methyl propiolate (0.53 mL) in trifluorotoluene (5 mL) wasstirred at 90° C. for 2 hours. The residue resulting from theconcentration of the reaction solution under reduced pressure waspurified by silica gel column chromatography (hexane:ethyl acetate=100:0to 70:30) to yield Compound 24A (130 mg).

(b) Methyl 5-formyl-4,7-dimethoxy-1-benzothiophene-3-carboxylate (24B)

Using Compound 24A (130 mg) obtained above and according to the sameprocedure as Reference example 10a, Compound 24B (96 mg) was obtained.

(c) Methyl5-{[(2,2-dimethoxyethyl)amino]methyl}-4,7-dimethoxy-1-benzothiophene-3-carboxylate(24C)

Using Compound 24B (96 mg) obtained above and according to the samemethod as Reference example 10b, Compound 24C was obtained as a crudeproduct. The whole amount thereof was used in the next reaction withoutfurther purification.

(d) Methyl5-({(2,2-dimethoxyethyl)[(2-nitrophenyl)sulfonyl]amino}methyl)-4,7-dimethoxy-1-benzothiophene-3-carboxylate(24D)

Using the crude product of Compound 24C obtained above and according tothe same procedure as Reference example 10c, Compound 24D (174 mg) wasobtained.

(e) 4,9-Dimethoxythieno[2,3-g]isoquinoline-3-carboxylic acid (24E)

To a solution of Compound 24D (174 mg) (which was obtained above) in1,4-dioxane (1 mL) was added 35% hydrochloric acid (1 mL), and then thereaction mixture was heated at reflux for 5 hours. The reaction solutionwas poured into iced water, and then the precipitated solid was removedby Celite filtration. The filtrate was neutralized with 28% ammoniawater, and then extracted with ethyl acetate. The organic layer wasdried over anhydrous sodium sulfate, filtered, and then concentratedunder reduced pressure. The resulting residue was recrystallized from amixed solution of ethyl acetate and hexane to yield Compound 24E (7 mg).

(f) (4,9-Dimethoxythieno[2,3-g]isoquinolin-3-yl)(morpholin-4-yl)methanone (24F)

Using the above-described Compound 24E (7 mg) and according to the sameprocedure as Reference example 6a, Compound 24F (8 mg) was obtained.

(g) 3-(Morpholin-4-ylcarbonyl)thieno[2,3-g]isoquinoline-4,9-dione (24G)

Using the above-described Compound 24F (8 mg) and according to the samemethod as Example 1, the title compound 24G (2.8 mg) was obtained.

(24A) ¹H-NMR (DMSO-d₆, δ ppm): 8.04 (1H, s), 6.93 (2H, d, J=8.5 Hz),6.89 (2H, d, J=8.5 Hz), 3.90 (3H, s), 3.82 (3H, s), 3.80 (3H, s).

MS (ESI+) 253 (M⁺+1).

(24B) ¹H-NMR (DMSO-d₆, δ ppm): 10.36 (1H, s), 8.38 (1H, s), 7.14 (1H,s), 4.08 (3H, s), 3.89 (3H, s), 3.84 (3H, s).

MS (ESI+) 281 (M⁺+1).

(24C) MS (ESI+) 370 (M⁺+1).

(24D) ¹H-NMR (DMSO-d₆, δ ppm): 8.10-8.07 (2H, m), 8.00 (1H, d, J=7.3Hz), 7.87 (1H, td, J=7.9, 1.2 Hz), 7.78 (1H, td, J=7.6, 1.2 Hz), 6.63(1H, s), 4.75 (2H, s), 4.37 (1H, t, J=5.2 Hz), 3.85 (3H, s), 3.81 (3H,s), 3.63 (3H, s), 3.34 (2H, d, J=4.9 Hz).

MS (ESI+) 555 (M⁺+1).

(24E) ¹H-NMR (DMSO-d₆, δ ppm): 13.40 (1H, br s), 9.58 (1H, s), 8.53 (1H,d, J=6.1 Hz), 8.26 (1H, s), 8.01 (1H, d, J=6.1 Hz), 4.16 (3H, s), 3.94(3H, s).

MS (ESI+) 290 (M⁺+1).

(24F) MS (ESI+) 359 (M⁺+1).

(24G) ¹H-NMR (DMSO-d₆, δ ppm): 9.29 (1H, s), 9.13 (1H, br s), 8.26 (1H,br s), 7.98 (1H, br s), 3.80-3.56 (4H, m), 3.49-3.40 (2H, m), 3.22-3.04(2H, m).

MS (ESI+) 329 (M⁺+1).

Example 232-[1-(morpholin-4-yl)ethyl]thieno[2,3-g]isoquinoline-4,9-dione (25C)

(a) 2-(1-Chloroethyl)-4,9-dimethoxythieno[2,3-g]isoquinoline (25A)

Using 1-(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)ethanol (36.5 mg)obtained in Example 13a and according to the same method as Referenceexample 7b, Compound 25A was obtained as a yellow solid.

(b) 4,9-Dimethoxy-2-[1-(morpholin-4-yl)ethyl]thieno[2,3-g]isoquinoline(25B)

Using Compound 25A (which was obtained above) and morpholine andaccording to the same method as Reference example 8, Compound 25B wasobtained (5.9 mg).

(c) 2-[1-(Morpholin-4-yl)ethyl]thieno[2,3-g]isoquinoline-4,9-dione (25C)

Using Compound 25B (5.7 mg) obtained above and according to the samemethod as Example 1, the title compound 25C was obtained as a yellowsolid (5.0 mg).

(25A) MS (ESI+) 308 (M⁺+1).

(25B) MS (ESI+) 359 (M⁺+1).

(25C) MS (ESI+) 329 (M⁺+1).

Reference Example 152-(chloromethyl)-4,9-dimethoxythieno[2,3-g]isoquinoline

Using (4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)methanol (190 mg)obtained in Reference example 12 and according to the same method asReference example 7b, the title compound was obtained as a crude product(265 mg). This was used in the next reaction without furtherpurification.

MS (ESI+) 294 (M⁺+1).

Example 242-{[ethyl(2-methoxyethyl)amino]methyl}thieno[2,3-g]isoquinoline-4,9-dione(26A)

(a)N-[(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)methyl]-N-ethyl-2-methoxyethaneamine(26A)

Using 2-(chloromethyl)-4,9-dimethoxythieno[2,3-g]isoquinoline (which wasobtained in Reference example 15) in acetonitrile (1.0 mL) andN-ethyl-2-methoxyethaneamine (14 μL) and according to the same method asReference example 8, Compound 26A was obtained (20 mg).

(b)2-{[Ethyl(2-methoxyethyl)amino]methyl}thieno[2,3-g]isoquinoline-4,9-dione(26B)

UsingN-[(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)methyl]-N-ethyl-2-methoxyethaneamine(20 mg) obtained above and according to the same method as Example 1,the title compound 26B was obtained as a yellow solid (13.2 mg).

(26A) MS (ESI+) 361 (M⁺+1).

(26B) MS (ESI+) 331 (M⁺+1).

Example 25cyclohexyl(ethyl)amino]methyl}thieno[2,3-g]isoquinoline-4,9-dione (27B)

(a)N-[(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)methyl]-N-ethylcyclohexylamine(27A)

Using 2-(chloromethyl)-4,9-dimethoxythieno[2,3-g]isoquinoline (30 mg)(which was obtained in Reference example 15) and N-ethylcyclohexylamine(17 μL) and according to the same method as Reference example 8,Compound 27A was obtained (16 mg).

(b)2-{[Cyclohexyl(ethyl)amino]methyl}thieno[2,3-g]isoquinoline-4,9-dione(27B)

UsingN-[(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)methyl]-N-ethylcyclohexylamine(16.0 mg) obtained above and according to the same method as Example 1,the title compound 27B was obtained as a yellow solid (13.2 mg).

(27A) MS (ESI+) 385 (M⁺+1).

(27B) MS (ESI+) 355 (M⁺+1).

Example 262-{[(2,2-difluoroethyl)amino]methyl}thieno[2,3-g]isoquinoline-4,9-dione(28B)

(a)N-[(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)methyl]-2,2-difluoroethaneamine(28A)

Using 2-(chloromethyl)-4,9-dimethoxythieno[2,3-g]isoquinoline (30 mg)(which was obtained in Reference example 15) and 2,2-difluoroethylamine(70 μL) and according to the same method as Reference example 8,Compound 28A was obtained (21 mg).

(b)2-{[(2,2-Difluoroethyl)amino]methyl}thieno[2,3-g]isoquinoline-4,9-dione(28B)

UsingN-[(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)methyl]-2,2-difluoroethaneamine(21 mg) obtained above and according to the same method as Example 1,the title compound 28B was obtained as a yellow solid (13.2 mg).

(28A) MS (ESI+) 385 (M⁺+1).

(28B) MS (ESI+) 309 (M⁺+1).

Example 272-[(4-acetylpiperazin-1-yl)methyl]thieno[2,3-g]isoquinoline-4,9-dione(29B)

(a)1-{4-[(4,9-Dimethoxythieno[2,3-g]isoquinolin-2-yl)methyl]piperazin-1-yl}ethanone(29A)

Using 2-(chloromethyl)-4,9-dimethoxythieno[2,3-g]isoquinoline (30 mg)(which was obtained in Reference example 15) and 1-acetylpiperazine (14mg) and according to the same method as Reference example 8, Compound29A was obtained (21 mg).

(b)2-[(4-Acetylpiperazin-1-yl)methyl]thieno[2,3-g]isoquinoline-4,9-dione(29B)

Using1-{4-[(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)methyl]piperazin-1-yl}ethanone(9.7 mg) obtained above and according to the same method as Example 1,the title compound 29B was obtained as a yellow solid (2.6 mg).

(29A) MS (ESI+) 386 (M⁺+1).

(29B) MS (ESI+) 356 (M⁺+1).

Example 28N-(2,2-difluoroethyl)-N-[(4,9-dihydrothieno[2,3-g]isoquinolin-2-yl)methyl]cyclohexanecarboxyamide(30B)

(a)N-(2,2-difluoroethyl)-N-[(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)methyl]cyclohexanecarboxyamide(30A)

UsingN-[(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)methyl]-2,2-difluoroethaneamine(36 mg) (which was obtained in Example 26a) and cyclohexanecarbonylchloride (16 μL) and according to the same method as Example 9a,Compound 30A was obtained (48 mg).

(b)N-(2,2-Difluoroethyl)-N-[(4,9-dihydrothieno[2,3-g]isoquinolin-2-yl)methyl]cyclohexanecarboxyamide(30B)

Using Compound 30A (48 mg) obtained above and according to the samemethod as Example 1, the title compound 30B was obtained as a yellowsolid (1.2 mg).

(30A) MS (ESI+) 449 (M⁺+1).

(30B) MS (ESI+) 419 (M⁺+1).

Example 29 4,9-dioxo-4,9-dihydrothieno[2,3-g]isoquinoline-2-carbonitrile(31D)

(a) 4,9-Dimethoxythieno[2,3-g]isoquinoline-2-carbonyl chloride (31A)

To 4,9-dimethoxythieno[2,3-g]isoquinoline-2-carboxylic acid (50 mg)(which was obtained in Reference example 10) was added thionyl chloride(2.0 mL), and the reaction mixture was heated at reflux for 1 hour.After the solvent was evaporated off, the resulting residue wassuspended in diethyl ether, and then collected by filtration to yieldCompound 31A (37 mg).

(b) 4,9-Dimethoxythieno[2,3-g]isoquinoline-2-carboxyamide (31B)

To Compound 31A (33 mg) (which was obtained above) was added 28% aqueousammonia solution (2.0 mL), and then the reaction mixture was stirred for1 hour. From the reaction solution, the solid was collected byfiltration to yield Compound 31B (20.0 mg).

(c) 4,9-Dimethoxythieno[2,3-g]isoquinoline-2-carbonitrile (31C)

To Compound 31B (20.0 mg) (which was obtained above) was addedphosphoryl chloride (1.0 mL), and then the reaction mixture was heatedat reflux for 1 hour. After the solvent was evaporated off, chloroformfollowed by aqueous saturated sodium hydrogen carbonate solution wereadded. After extraction with ethyl acetate two times, the resultingorganic layer was washed with water and saturated brine, and then driedover sodium sulfate. The solvent was then evaporated off. The resultingresidue was purified by silica gel column chromatography(chloroform/methanol) to yield Compound 31C (24 mg).

(d) 4,9-Dioxo-4,9-dihydrothieno[2,3-g]isoquinoline-2-carbonitrile (31D)

Using Compound 31C (24 mg) obtained above and according to the samemethod as Example 1, the title compound 31D was obtained as a yellowsolid (1.2 mg).

(31B) MS (ESI+) 289 (M⁺+1).

(31C) MS (ESI+) 304 (M⁺+1).

(31D) MS (ESI+) 241 (M⁺+1).

Example 30 2-(1-fluoroethyl)thieno[2,3-g]isoquinoline-4,9-dione (32B)

(a) 2-(1-Fluoroethyl)-4,9-dimethoxythieno[2,3-g]isoquinoline (32A)

To a solution of 1-(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)ethanol(46 mg) (which was obtained in Example 13a) in dichloromethane (1.0 mL),under ice-cooling, was added FLUOLEAD™ (66 mg), and then the reactionmixture was stirred for 1 hour. Aqueous sodium hydroxide solution (2 N)was added thereto. After extraction with ethyl acetate, the resultingorganic layer was washed with water and saturated brine, and then driedover sodium sulfate. The solvent was then evaporated off. The resultingresidue was purified by silica gel column chromatography(chloroform/methanol) to yield Compound 32A (24 mg).

(b) 2-(1-Fluoroethyl)thieno[2,3-g]isoquinoline-4,9-dione (32B)

Using Compound 32A (24 mg) obtained above and according to the samemethod as Example 1, the title compound 32B was obtained as a yellowsolid (1.2 mg).

(32A) MS (ESI+) 292 (M⁺+1).

(32B) MS (ESI+) 262 (M⁺+1).

Example 312-(3-ethyl-1,2,4-oxadiazol-5-yl)thieno[2,3-g]isoquinoline-4,9-dione(33B)

(a)2-(3-Ethyl-1,2,4-oxadiazol-5-yl)-4,9-dimethoxythieno[2,3-g]isoquinoline(33A)

To a solution of 4,9-dimethoxythieno[2,3-g]isoquinoline-2-carbonylchloride (960 mg) (which was obtained in Example 29a) in chloroform (40mL) were added N-hydroxypropionamidine (288 mg) and Hunig's base (1.6mL), and then the reaction mixture was stirred at room temperature for 1hour. Aqueous saturated sodium hydrogen carbonate solution was added tothe reaction solution, and then extraction with ethyl acetate wasperformed. The resulting organic layer was washed with saturated brine,and then dried over sodium sulfate. The solvent was then evaporated off.To the solution of the resulting residue in THF (20 mL),tetra-N-butylammonium fluoride (2.5 mL) was added, followed by heatingat reflux for 1 hour. The reaction solution was returned to roomtemperature, aqueous saturated sodium hydrogen carbonate solution wasadded thereto, and then extraction with ethyl acetate was performed. Theresulting organic layer was washed with saturated brine, and then driedover sodium sulfate. The solvent was then evaporated off. The resultingresidue was suspended in methanol and collected by filtration to yieldCompound 33A (285 mg).

(b) 2-(3-Ethyl-1,2,4-oxadiazol-5-yl)thieno[2,3-g]isoquinoline-4,9-dione(33B)

Using Compound 33A (50 mg) obtained above and according to the samemethod as Example 1, the title compound 33B was obtained as a yellowsolid (32 mg).

(33A) MS (ESI+) 342 (M⁺+1).

(33B) MS (ESI+) 312 (M⁺+1).

Example 32 2-(morpholin-4-yl)thieno[2,3-g]isoquinoline-4,9-dione (34D)

(a) Tert-butyl (4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)carbamate(34A)

A solution of 4,9-dimethoxythieno[2,3-g]isoquinoline-2-carboxylic acid(200 mg) (which was obtained in Reference example 10),diisopropylethylamine (120 μL), diphenylphosphoryl azide (310 μL), andtert-butyl alcohol (1 mL) in NMP (1 mL) was stirred at room temperaturefor 30 minutes, and then heated at reflux for 2 hours. The reactionsolution was purified by silica gel column chromatography (hexane:ethylacetate=50:50 to 0:100) to yield Compound 34A (140 mg).

(b) 4,9-Dimethoxythieno[2,3-g]isoquinoline-2-amine.dihydrochloride (34B)

To Compound 34A (140 mg) obtained above was added 4 mol/L solution (3mL) of hydrogen chloride in 1,4-dioxane, and then the reaction mixturewas stirred at room temperature for 1 hour. The reaction solution wasconcentrated under reduced pressure to yield Compound 34B (110 mg).

(c) 4,9-Dimethoxy-2-(morpholin-4-yl)thieno[2,3-g]isoquinoline (34C)

A solution of Compound 34B (50 mg) (which was obtained above),diisopropylethylamine (260 μL), and bisbromoethyl ether (94 μL) in DMF(1.5 mL) was stirred at 90° C. for 2 hours. Cesium carbonate (100 mg)was added to the reaction solution, which was then stirred at 120° C.for another 3 hours. Water (5 mL) was added to the reaction solution,which was then extracted with ethyl acetate. The organic layer was driedover anhydrous sodium sulfate, filtered, and then concentrated underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate=100:0 to 0:100) to yield amixture comprising Compound 34C.

(d) 2-(Morpholin-4-yl)thieno[2,3-g]isoquinoline-4,9-dione (34D)

Using a mixture comprising Compound 34C obtained above and according tothe same method as Example 1, the title compound 34D was obtained (1.3mg).

(34A) MS (ESI+) 361 (M⁺+1).

(34B) MS (ESI+) 261 (M⁺+1).

(34C) MS (ESI+) 331 (M⁺+1).

(34D) MS (ESI+) 301 (M⁺+1).

Reference Example 16 4,9-dimethoxythieno[3,2-g]isoquinoline-2-carboxylicacid (35E)

(a) Methyl5-(1-hydroxy-2-nitroethyl)-4,7-dimethoxy-1-benzothiophene-2-carboxylate(35A)

A solution of methyl5-formyl-4,7-dimethoxy-1-benzothiophene-2-carboxylate (10 g) (which wasobtained in Reference example 10a) and diisopropylethylamine (40 mL) innitromethane (200 mL) was stirred at room temperature for 4 hours.Thirty percent aqueous sodium hydrogen sulfite solution (200 mL) wasadded to the reaction solution, it was stirred for 30 minutes, and thenextraction with ethyl acetate was performed. The organic layer waswashed with saturated sodium hydrogen carbonate, dried over anhydroussodium sulfate, filtered, and then concentrated under reduced pressureto yield Compound 35A. This product was used in the next reactionwithout further purification.

(b) Methyl5-(2-amino-1-hydroxyethyl)-4,7-dimethoxy-1-benzothiophene-2-carboxylate(35B)

To a solution of Compound 35A (which was obtained above) and nickelchloride hexahydrate (33.9 g) in methanol (300 mL), under ice-cooling,was added portionwise sodium borohydride (5.4 g) over a period of 30 ormore minutes, and then the reaction mixture was stirred for anotherhour. Water (200 mL) was added to the reaction solution, and then theprecipitated solid was removed through Celite filtration. After methanolwas evaporated off under reduced pressure, the aqueous layer wasextracted with ethyl acetate, and then the organic layer was washed with28% ammonium water. The organic layer was dried over anhydrous sodiumsulfate, filtered, and then concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(hexane:ethyl acetate=20:80 to 0:100, then chloroform:methanol=100:0 to90:10) to yield Compound 35B (9 g).

(c) Methyl5-[2-(formylamino)-1-hydroxyethyl]-4,7-dimethoxy-1-benzothiophene-2-carboxylate(35C)

A solution of Compound 35B (9 g) (which was obtained above) and aceticanhydride (450 μL) in formic acid (100 mL) was heated at reflux for 3hours. To the residue resulting from the concentration of the reactionsolution under reduced pressure, saturated potassium carbonate/methanolsolution (100 mL) was added, and then the reaction mixture was stirredat room temperature for 2 hours. The reaction solution was filteredthrough Celite, and then the filtrate was concentrated under reducedpressure. Water (100 mL) was added to the resulting residue, and then itwas extracted with ethyl acetate. The organic layer was dried overanhydrous sodium sulfate, filtered, and then concentrated under reducedpressure. The resulting residue recrystallized from mixed solution ofethyl acetate and hexane to yield Compound 35C (8 g).

(d) Methyl 4,9-dimethoxythieno[3,2-g]isoquinoline-2-carboxylate (35D)

A solution of Compound 35C (1.7 g) (which was obtained above) andphosphorus oxychloride (1.4 mL) in acetonitrile (5 mL) was heated atreflux for 3 hours. The residue resulting from the concentration of thereaction solution under reduced pressure was neutralized with aqueoussaturated sodium hydrogen carbonate solution. The aqueous layer wasextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate, filtered, and then concentrated under reduced pressure.The resulting residue was purified by silica gel column chromatography(hexane:ethyl acetate=100:0 to 50:50) to Compound 35D to yield (320 mg).

(e) 4,9-Dimethoxythieno[3,2-g]isoquinoline-2-carboxylic acid (35E)

Using Compound 35D (320 mg) obtained above and according to the samemethod as Reference example 5, the title compound 35E was obtained (297mg).

(35A) ¹H-NMR (DMSO-d₆, δ ppm): 8.13 (1H, s), 7.20 (1H, s), 6.19 (1H, d,J=5.5 Hz), 5.71-5.65 (1H, m), 4.81-4.6 (2H, m), 3.97 (3H, s), 3.94 (3H,s), 3.89 (3H, s).

MS (ESI+) 342 (M⁺+1).

(35B) MS (ESI+) 312 (M⁺+1).

(35C) ¹H-NMR (DMSO-d₆, δ ppm): 8.21 (1H, s), 8.09 (1H, s), 6.97 (1H, s),6.05-5.94 (1H, m), 5.27-5.19 (1H, m), 3.97 (3H, s), 3.95 (3H, s), 3.93(3H, s), 3.80-3.72 (1H, m), 3.58-3.49 (1H, m).

MS (ESI+) 340 (M⁺+1).

(35D) ¹H-NMR (DMSO-d₆, δ ppm): 9.61 (1H, s), 8.55 (1H, d, J=6.1 Hz),8.36 (1H, s), 8.04 (1H, d, J=6.1 Hz), 4.19 (3H, s), 4.14 (3H, s), 3.94(3H, s).

MS (ESI+) 304 (M⁺+1).

(35E) ¹H-NMR (DMSO-d₆, δ ppm): 14.03 (1H, br s), 9.58 (1H, s), 8.53 (1H,s), 8.17 (1H, s), 8.02 (1H, s), 4.18 (3H, s), 4.12 (3H, s).

MS (ESI+) 290 (M⁺+1).

Reference Example 171-(4,9-dimethoxythieno[3,2-g]isoquinolin-2-yl)ethanone (36B)

Using 4,9-dimethoxythieno[3,2-g]isoquinoline-2-carboxylic acid (29 mg)obtained in Reference example 16 and according to the same method asReference example 6, the title compound 36B was obtained.

(36A) MS (ESI+) 359 (M⁺+1).

(36B) MS (ESI+) 288 (M⁺+1).

Example 33 2-acetylthieno[3,2-g]isoquinoline-4,9-dione

Using 1-(4,9-dimethoxythieno[3,2-g]isoquinolin-2-yl)ethanone obtained inReference example 17 and according to the same method as Example 1,synthesis was carried out to yield the title compound (5.5 mg).

¹H-NMR (DMSO-d₆, δ ppm): 9.26 (1H, s), 9.10 (1H, br s), 7.96 (1H, br s),7.55 (1H, s), 6.15 (1H, d, J=4.9 Hz), 5.09 (1H, br s), 1.48 (3H, d,J=6.1 Hz).

MS (ESI+) 258 (M⁺+1).

Example 34 1-(4,9-dimethoxythieno[3,2-g]isoquinolin-2-yl)ethanol (37B)

Using 1-(4,9-dimethoxythieno[3,2-g]isoquinolin-2-yl)ethanone (40 mg)obtained in Reference example 17 and according to the same method asExample 2, synthesis was carried out to yield the title compound 37B (12mg).

(37A) MS (ESI+) 290 (M⁺+1).

(37B) ¹H-NMR (DMSO-d₆, δ ppm): 9.26 (1H, s), 9.10 (1H, br s), 7.96 (1H,br s), 7.55 (1H, s), 6.15 (1H, d, J=4.9 Hz), 5.09 (1H, br s), 1.48 (3H,d, J=6.1 Hz).

MS (ESI+) 260 (M⁺+1).

Example 35N-[(4,9-dimethoxythieno[3,2-g]isoquinolin-2-yl)methyl]-2,2-difluoroethaneamine(38E)

(a) (4,9-Dimethoxythieno[3,2-g]isoquinolin-2-yl)methanol (38A)

Using 4,9-dimethoxythieno[3,2-g]isoquinoline-2-carboxylic acid (60 mg)obtained in Reference example 16 and according to the same method asReference example 12, synthesis was carried out to yield Compound 38A(37 mg).

(b) 4,9-Dimethoxythieno[3,2-g]isoquinoline-2-carbaldehyde (38B)

A suspension of Compound 38A (37 mg) (which was obtained above) andmanganese dioxide (240 mg) in chloroform (2 mL) was stirred at roomtemperature for 3 hours. The reaction solution was filtered throughCelite, and then the filtrate was concentrated under reduced pressure toyield a crude product of Compound 38B (36 mg). The whole amount of thisproduct was used in the next reaction without further purification.

(c)(E)-N-(2,2-difluoroethyl)-1-(4,9-dimethoxythieno[3,2-g]isoquinolin-2-yl)methanimine(38C)

To a solution of the crude product 38B (36 mg) (which was obtainedabove), difluoroethylamine (19 μL), and acetic acid (23 μL) in THF (2mL) was added sodium triacetoxyborohydride (57 mg), and then thereaction mixture was stirred at room temperature for 1 hour. Aqueoussaturated sodium hydrogen carbonate solution (2 mL) was added to thereaction solution, which was then extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate, filtered, andthen concentrated under reduced pressure to yield Compound 38C as acrude product. The whole amount of this product was used in the nextreaction without further purification.

(d)N-[(4,9-dimethoxythieno[3,2-g]isoquinolin-2-yl)methyl]-2,2-difluoroethaneamine(38D)

To a solution of the crude product 38C in THF (2 mL) was added sodiumborohydride (15 mg), and then the reaction mixture was stirred at roomtemperature for 2 hours. After that, methanol (0.2 mL) was added to thereaction solution, and then stirred for another 10 minutes.

Water was added to the reaction solution. After extraction with ethylacetate, the organic layer was dried over anhydrous sodium sulfate,filtered, and then concentrated under reduced pressure to yield Compound38D as a crude product. The whole amount of this product was used in thenext reaction without further purification.

(e)2-{[(2,2-Difluoroethyl)amino]methyl}thieno[3,2-g]isoquinoline-4,9-dione(38E)

Using the crude product 38D obtained above and according to the samemethod as Example 1, the title compound 38E was obtained (2.3 mg).

(38A) MS (ESI+) 276 (M⁺+1).

(38B) MS (ESI+) 274 (M⁺+1).

(38C) MS (ESI+) 337 (M⁺+1).

(38D) MS (ESI+) 339 (M⁺+1).

(38E) MS (ESI+) 309 (M⁺+1).

Reference Example 18 1-(4,9-dimethoxythieno[3,2-g]quinolin-2-yl)ethanol(39E)

(a) Methyl 4,9-dimethoxy-[3,2-g]quinoline-2-carboxylate (39A)

To a solution of methyl6-amino-4,7-dimethoxy-1-benzothiophene-2-carboxylate (1.2 g) (which wasobtained in Reference example 3) in acetic acid (4.0 mL) were addedaqueous hydrogen bromide solution (4.0 mL) and 2-propenal (670 μL), andthen the reaction mixture was stirred at 70° C. for 3 hours. After itwas returned to room temperature, the solvent was evaporated off toyield Compound 39A as a crude product. This was used in the nextreaction without further purification.

(b) 4,9-Dimethoxythieno[3,2-g]quinoline-2-carboxylic acid (39B)

Using Compound 39A obtained above and according to the same method asReference example 5, Compound 39B was obtained as a crude product. Thiswas used in the next reaction without further purification.

(c) (4,9-Dimethoxythieno[3,2-g]quinolin-2-yl) (morpholin-4-yl)methanone(39C)

Using Compound 39B obtained above and according to the same method asReference example 6a, Compound 39C was obtained (110 mg).

(d) 1-(4,9-Dimethoxythieno[3,2-g]quinolin-2-yl)ethanone (39D)

Using Compound 39C (110 mg) obtained above and according to the samemethod as Reference example 6b, Compound 39D was obtained as a crudeproduct. This was used in the next reaction without furtherpurification.

(e) 1-(4,9-Dimethoxythieno[3,2-g]quinolin-2-yl)ethanol (39E)

Using Compound 39D obtained above and according to the same method asExample 2a, the title compound 39E was obtained as a crude product (90mg). This was used in the next reaction without further purification.

(39A) MS (ESI+) 304 (M⁺+1).

(39B) MS (ESI+) 290 (M⁺+1).

(39C) MS (ESI+) 359 (M⁺+1).

(39D) MS (ESI+) 288 (M⁺+1).

(39E) MS (ESI+) 290 (M⁺+1).

Example 36 2-acetylthieno[3,2-g]quinoline-4,9-dione

Using 1-(4,9-dimethoxythieno[3,2-g]quinolin-2-yl)ethanone (17 mg)obtained in Reference example 18d and according to the same method asExample 1, the title compound was obtained (9.3 mg).

MS (ESI+) 258 (M⁺+1).

Example 37 2-(1-hydroxyethyl)thieno[3,2-g]quinoline-4,9-dione

Using 1-(4,9-dimethoxythieno[3,2-g]quinolin-2-yl)ethanol obtained inReference example 18 and according to the same method as Example 1, thetitle compound was obtained (1.9 mg).

¹H-NMR (DMSO-d₆, δ ppm): 9.01 (1H, d, J=3.1 Hz), 8.46 (1H, dd, J=7.9,1.8 Hz), 7.85 (1H, dd, J=7.9, 4.9 Hz), 7.53 (1H, s), 6.13 (1H, s), 5.07(1H, d, J=6.1 Hz), 1.48 (3H, d, J=7.3 Hz).

MS (ESI+) 260 (M⁺+1).

Example 38 2-(1-methoxyethyl)thieno[3,2-g]quinoline-4,9-dione (40B)

(a) (4,9-Dimethoxythieno-2-(1-methoxyethyl)thieno[3,2-g]quinoline (40A)

Using 1-(4,9-dimethoxythieno[3,2-g]quinolin-2-yl)ethanol (90 mg) (whichwas obtained in Reference example 18e) and methyl iodide (80 μL) andaccording to the same method as Reference example 13c, Compound 40A wasobtained (95 mg).

(b) 2-(1-Methoxyethyl)thieno[3,2-g]quinoline-4,9-dione (40B)

Using Compound 40A (95 mg) obtained above and according to the samemethod as Example 1, the title compound 40B was obtained (24.8 mg).

(40A) MS (ESI+) 304 (M⁺+1).

(40B) ¹H-NMR (DMSO-d₆, δ ppm): 9.02 (1H, dd, J=4.6, 1.5 Hz), 8.47 (1H,dd, J=7.9, 1.2 Hz), 7.86 (1H, dd, J=7.9, 4.3 Hz), 7.65 (1H, s), 4.80(1H, q, J=6.3 Hz), 3.31 (3H, s), 1.50 (3H, d, J=6.1 Hz).

MS (ESI+) 274 (M⁺+1).

Example 392-[(3,5-dimethylpiperidin-5-yl)carbonyl]thieno[3,2-g]quinoline-4,9-dione(41B)

(a) (4,9-Dimethoxythieno[3,2-g]quinolin-2-yl)(3,5-dimethylpiperidin-5-yl)methanone (41A)

Using 4,9-dimethoxythieno[3,2-g]quinoline-2-carboxylic acid (89 mg)(which was obtained in Reference example 18b) and 3,5-dimethylpiperidine(83 μL) and according to the same method as Reference example 6a,Compound 41A was obtained (18 mg).

(b)2-[(3,5-Dimethylpiperidin-5-yl)carbonyl]thieno[3,2-g]quinoline-4,9-dione(41B)

Using Compound 41A (18 mg) obtained above and according to the samemethod as Example 1, the title compound 41B was obtained (10.5 mg).

(41A) MS (ESI+) 385 (M⁺+1).

(41B) MS (ESI+) 355 (M⁺+1).

Example 40N-(2,2-difluoroethyl)-4,9-dioxo-4,9-dihydroxythieno[3,2-g]quinoline-2-carboxyamide(42B)

(a)N-(2,2-Difluoroethyl)-4,9-dimethoxythieno[3,2-g]quinoline-2-carboxyamide(42A)

Using 4,9-dimethoxythieno[3,2-g]quinoline-2-carboxylic acid (73 mg)obtained in Reference example 18b and according to the same method asExample 21a, Compound 42A was obtained (30 mg).

(b)N-(2,2-Difluoroethyl)-4,9-dioxo-4,9-dihydroxythieno[3,2-g]quinoline-2-carboxyamide(42B)

Using Compound 42A (30 mg) obtained above and according to the samemethod as Example 1, the title compound 42B was obtained (21.9 mg).

(42A) MS (ESI+) 353 (M⁺+1).

(42B) MS (ESI+) 323 (M⁺+1).

Example 41 tert-butyl(4,9-dioxo-4,9-dihydrothieno[3,2-g]quinolin-2-yl)methylcarbamate (43C)

(a) Tert-butyl (4,9-dimethoxythieno[3,2-g]quinolin-2-yl) carbamate (43A)

To a solution of 4,9-dimethoxythieno[3,2-g]quinoline-2-carboxylic acid(22 mg) (which was obtained in Reference example 18b) in tert-butanol(1.0 mL) were added triethylamine (42 μL) and diphenylphosphoryl azide(24 μL), and then the reaction mixture was stirred for 12 hours. Waterwas added thereto, and then extracted with ethyl acetate. The resultingorganic layer was washed with saturated brine, and then dried oversodium sulfate. The solvent was then evaporated off. The resultingresidue was purified by silica gel column chromatography (hexane/ethylacetate) to yield Compound 43A (7.0 mg).

(b) Tert-butyl (4,9-dimethoxythieno[3,2-g]quinolin-2-yl)methylcarbamate(43B)

To a solution of Compound 43A (7.0 mg) (which was obtained above) indimethylformamide (500 μL), under ice-cooling, was added sodium hydride(1.0 mg), and then the reaction mixture was stirred at room temperaturefor 20 minutes. Subsequently, methyl iodide (3.0 μL) was added thereto,and then the reaction mixture was stirred for 1 hour. After that,aqueous saturated ammonium chloride solution was added thereto, and thenextraction with ethyl acetate was performed. The resulting organic layerwas washed with water and saturated brine, and then dried over sodiumsulfate. The solvent was then evaporated off. The resulting residue waspurified by silica gel column chromatography (hexane/ethyl acetate) toyield Compound 43B (3.7 mg).

(c) Tert-butyl(4,9-dioxo-4,9-dihydrothieno[3,2-g]quinolin-2-yl)methylcarbamate (43C)

Using Compound 43B (3.7 mg) obtained above and according to the samemethod as Example 1, the title compound 43C was obtained (3.8 mg).

(43A) MS (ESI+) 361 (M⁺+1).

(43B) MS (ESI+) 375 (M⁺+1).

(43C) MS (ESI+) 345 (M⁺+1).

Reference Example 19 methyl 4,7-dimethoxy-1-benzofuran-2-carboxylate

To a solution of methyl glycolate (25.0 g) in THF (400 mL), underice-cooling, sodium hydride (13.1 g) was added in 10 parts, and thereaction mixture was stirred at room temperature for 1 hour. To thereaction solution ice-cooled again, 3,6-dimethoxy-2-nitrobenzaldehyde(48.8 g) was added in 10 parts, and the reaction mixture was heated andstirred at 60° C. for 6 hours. The reaction solution was cooled to roomtemperature, aqueous saturated sodium bicarbonate (500 mL) was addedthereto, and then extraction with chloroform (2×500 mL) was performed.The resulting organic layer was washed with saturated brine, dried oversodium sulfate, and then purified by amino-silica gel chromatography(chloroform). The resulting crude product was suspended in methanol,stirred at room temperature for 1 hour, filtered, and then dried toyield the title compound as an opaque white solid (7.7 g).

¹H-NMR (DMSO-d₆, δ ppm): 7.63 (1H, s), 7.03 (1H, d, J=8.4 Hz), 6.74 (1H,d, J=8.4 Hz), 3.90 (3H, s), 3.88 (3H, s), 3.87 (3H, s).

Reference Example 20 methyl5-amino-4,7-dimethoxy-1-benzofuran-2-carboxylate (45A) Reference Example21 methyl 6-amino-4,7-dimethoxy-1-benzofuran-2-carboxylate (45B)

Using methyl 4,7-dimethoxy-1-benzofuran-2-carboxylate (5.00 g) obtainedin Reference example 19 and according to the same methods as Referenceexamples 2 and 3, Compound 45A was obtained as a brown powder (1.38 g)and Compound 45B was obtained as an opaque white solid (707 mg).

(45A) ¹H-NMR (DMSO-d₆, δ ppm): 7.63 (1H, s), 6.60 (1H, s), 4.76 (2H, s),3.87 (3H, s), 3.84 (3H, s), 3.79 (3H, s).

(45B) ¹H-NMR (DMSO-d₆, δ ppm): 7.46 (1H, s), 6.28 (1H, s), 5.48 (2H, s),3.83 (3H, s), 3.79 (3H, s), 3.79 (3H, s).

Reference Example 22 methyl4,9-dimethoxyfuro[2,3-g]quinoline-2-carboxylate (46B)

(a) Methyl4,7-dimethoxy-5-(prop-2-yn-1-ylamino)-1-benzofuran-2-carboxylate (46A)

Using Compound 45A (920 mg) obtained in Reference example 20 andaccording to the same method as Reference example 4a, Compound 46A wasobtained as a yellow powder (477 mg).

(b) Methyl 4,9-dimethoxyfuro[2,3-g]quinoline-2-carboxylate (46B)

Using Compound 46A (440 mg) and according to the same method asReference example 4b, Compound 46B was obtained as a yellow solid (112mg).

(46A) ¹H-NMR (DMSO-d₆, δ ppm): 7.70 (1H, s), 6.70 (1H, s), 5.31 (1H, s),4.00 (2H, brs), 3.91 (3H, s), 3.88 (3H, s), 3.82 (3H, s), 3.03 (1H, s).

MS (ESI+) 290 (M⁺+1).

(46B) ¹H-NMR (DMSO-d₆, δ ppm): 8.90 (1H, d, J=4.0 Hz), 8.61 (1H, d,J=8.4 Hz), 7.94 (1H, s), 7.53 (1H, dd, J=4.0, 8.4 Hz), 4.31 (3H, s),4.27 (3H, s), 3.97 (3H, s).

MS (ESI+) 288 (M⁺+1).

Reference Example 23 4,9-dimethoxyfuro[2,3-g]quinoline-2-carboxylic acid

Using Compound 46B (110 mg) obtained in Reference example 22 andaccording to the same method as Reference example 5, the title compoundwas obtained as a brown solid (100 mg).

MS (ESI+) 274 (M⁺+1).

Reference Example 24 1-(4,9-dimethoxyfuro[2,3-g]quinolin-2-yl)ethanone(47B)

(a) (4,9-Dimethoxyfuro[2,3-g]quinolin-2-yl) (morpholin-4-yl)methanone(47A)

Using 4,9-dimethoxyfuro[2,3-g]quinoline-2-carboxylic acid (100 mg)obtained in Reference example 23 and according to the same method asReference example 6a, Compound 47A was obtained as a brown solid (90.1mg).

(b) 1-(4,9-Dimethoxyfuro[2,3-g]quinolin-2-yl)ethanone (47B)

Using Compound 47A (89.0 mg) obtained above and according to the samemethod as Reference example 6b, Compound 47B was obtained as a yellowsolid (67.0 mg).

(47A) ¹H-NMR (DMSO-d₆, δ ppm): 8.89 (1H, dd, J=1.6, 4.0 Hz), 8.61 (1H,dd, J=1.6, 8.4 Hz), 7.70 (1H, s), 7.54 (1H, dd, J=4.0, 8.4 Hz), 4.25(3H, s), 4.23 (3H, s), 3.98-3.90 (8H, m).

MS (ESI+) 343 (M⁺+1).

(47B) ¹H-NMR (DMSO-d₆, δ ppm): 8.90 (1H, d, J=4.0 Hz), 8.61 (1H, d,J=8.4 Hz), 8.29 (1H, s), 7.57 (1H, dd, J=4.0, 8.4 Hz), 4.31 (3H, s),4.24 (3H, s), 2.65 (3H, s).

MS (ESI+) 272 (M⁺+1).

Example 42 2-acetylfuro[2,3-g]quinoline-4,9-dione

Using 1-(4,9-dimethoxyfuro[2,3-g]quinolin-2-yl)ethanone (24.0 mg)obtained in Reference example 24 and according to the same method asExample 1, the title compound was obtained as a yellow powder (15.7 mg).

MS (ESI+) 242 (M⁺+1).

Example 43 2-(1-hydroxyethyl)furo[2,3-g]quinoline-4,9-dione (48B)

(a) 1-(4,9-Dimethoxyfuro[2,3-g]quinolin-2-yl)ethanol (48A)

Using 1-(4,9-dimethoxyfuro[2,3-g]quinolin-2-yl)ethanone (42.2 mg)obtained in Reference example 24 and according to the same method asExample 2a, Compound 48A was obtained as a yellow solid (38.3 mg).

(b) 2-(1-Hydroxyethyl)furo[2,3-g]quinoline-4,9-dione (48B)

Using Compound 48A and according to the same method as Example 1, thetitle compound 48B was obtained as a yellow powder (29.2 mg).

(48A) MS (ESI+) 274 (M⁺+1).

(48B) MS (ESI+) 244 (M⁺+1).

Reference Example 25 methyl5-formyl-4,7-dimethoxy-1-benzofuran-2-carboxylate (49A) ReferenceExample 26 methyl 6-formyl-4,7-dimethoxy-1-benzofuran-2-carboxylate(49B)

Under nitrogen atmosphere, to a solution of methyl4,7-dimethoxy-1-benzofuran-2-carboxylate (9.00 mg) (which was obtainedin Reference example 19) in dichloromethane (200 mL) was added dropwisetitanium tetrachloride (12.3 mL) at 0° C., and then the reaction mixturewas stirred for 30 minutes. 1,1-Dichloromethylmethyl ether (4.50 mL) wasadded dropwise, stirred at 0° C. for 1 hour, and then stirred at roomtemperature for 3 hours. The reaction solution was poured into icedwater, and then extracted with chloroform. The organic layer was driedover anhydrous sodium sulfate, filtered, and then concentrated underreduced pressure. The resulting residue was purified by silica gelchromatography (ethyl acetate/chloroform) to yield Compound 49A (6.20 g)and Compound 49B (0.68 g) as a yellow solid, respectively.

(49A) MS (ESI+) 265 (M⁺+1).

(49B) MS (ESI+) 265 (M⁺+1).

Reference Example 27 4, 9-dimethoxyfuro[2,3-g]isoquinoline-2-carboxylicacid (50D)

(a) Methyl5-{[(2,2-dimethoxyethyl)amino]methyl}-4,7-dimethoxy-1-benzofuran-2-carboxylate(50A)

Using methyl 5-formyl-4,7-dimethoxy-1-benzofuran-2-carboxylate (1.30 g)obtained in Reference example 25 and according to the same method asReference example 10b, Compound 50A (1.50 g) was obtained.

(b) Methyl5-({(2,2-dimethoxyethyl)[(4-methylphenyl)sulfonyl]amino}methyl)-4,7-dimethoxy-1-benzofuran-2-carboxylate(50B)

To a solution of Compound 50A (1.50 g) (which was obtained above) inchloroform (50 mL) were added aqueous saturated sodium hydrogencarbonate solution (200 mL) and p-toluenesulfonyl chloride (1.88 g), andthen the reaction mixture was stirred at room temperature for 2 hours.Aqueous saturated sodium hydrogen carbonate solution (50 mL) was addedto the reaction solution, which was then extracted with chloroform. Theorganic layer was dried over anhydrous sodium sulfate, filtered, andthen concentrated under reduced pressure. The resulting residue waspurified by silica gel chromatography (methanol/chloroform) to yieldCompound 50B (1.67 g).

(c) Methyl 4,9-dimethoxyfuro[2,3-g]isoquinoline-2-carboxylate (50C)

Under nitrogen atmosphere, to a solution of Compound 50B (1.67 g) (whichwas obtained above) in methylene chloride (50 mL) was added titaniumtetrachloride (1.62 mL) at 0° C., and then the reaction mixture wasstirred at room temperature for 6 hours. The reaction solution waspoured into iced water, neutralized with sodium hydrogen carbonate(pH=7-8), and then extracted with chloroform. The organic layer wasdried over anhydrous sodium sulfate, filtered, and then concentratedunder reduced pressure. The resulting residue was purified by silica gelchromatography (ethyl acetate/chloroform) to yield Compound 50C (0.28g).

(d) 4,9-Dimethoxyfuro[2,3-g]isoquinoline-2-carboxylic acid (50D)

Using Compound 50C (0.28 g) obtained above and according to the samemethod as Reference example 5, Compound 50D (0.23 g) was obtained.

(50A) MS (ESI+) 354 (M⁺+1).

(50B) MS (ESI+) 508 (M⁺+1).

(50C) MS (ESI+) 288 (M⁺+1).

(50D) MS (ESI+) 273 (M⁺+1).

Reference Example 281-(4,9-dimethoxyfuro[2,3-g]isoquinolin-2-yl)ethanone (51B)

(a) (4,9-Dimethoxyfuro[2,3-g]isoquinolin-2-yl) (morpholin-4-yl)methanone(51A)

Using 4,9-dimethoxyfuro[2,3-g]isoquinoline-2-carboxylic acid (0.23 g)obtained in Reference example 27 and according to the same method asReference example 6a, Compound 51A was obtained as a yellow powder (0.24g).

(b) 1-(4,9-Dimethoxyfuro[2,3-g]isoquinolin-2-yl)ethanone (51B)

Using Compound 51A (0.24 g) obtained above and according to the samemethod as Reference example 6b, Compound 51B was obtained as a yellowpowder (0.18 g).

(51A) MS (ESI+) 343 (M⁺+1).

(51B) MS (ESI+) 272 (M⁺+1).

Example 44 2-acetylfuro[2,3-g]isoquinoline-4,9-dione

Using 1-(4,9-dimethoxyfuro[2,3-g]isoquinolin-2-yl)ethanone (70 mg)obtained in Reference example 28 and according to the same method asExample 1, the title compound was obtained as a yellow powder (38 mg).

MS (ESI+) 242 (M⁺+1).

Example 45 2-(1-hydroxyethyl)furo[2,3-g]isoquinoline-4,9-dione (52B)

(a) 1-(4,9-Dimethoxyfuro[2,3-g]isoquinolin-2-yl)ethanol (52A)

Using 1-(4,9-dimethoxyfuro[2,3-g]isoquinolin-2-yl)ethanone (52.0 mg)obtained in Reference example 28 and according to the same method asExample 2a, Compound 52A was obtained as a yellow powder (44.0 mg).

(b) 2-(1-Hydroxyethyl)furo[2,3-g]isoquinoline-4,9-dione (52B)

Using Compound 52A (44.0 mg) obtained above and according to the samemethod as Example 1, Compound 52B was obtained as a yellow powder (29.0mg).

(52A) MS (ESI+) 274 (M⁺+1).

(52B) MS (ESI+) 244 (M⁺+1).

Example 46N-(2,2-difluoroethyl)-4,9-dioxo-4,9-dihydrofuro[2,3-g]isoquinoline-2-carboxamide(53B)

(a)N-(2,2-Difluoroethyl)-4,9-dimethoxyfuro[2,3-g]isoquinoline-2-carboxamide(53A)

Using 4,9-dimethoxyfuro[2,3-g]isoquinoline-2-carboxylic acid (7.9 mg)obtained in Reference example 27 and according to the same method asExample 21a, Compound 53A (3.9 mg) was obtained.

(b)N-(2,2-Difluoroethyl)-4,9-dioxo-4,9-dihydrofuro[2,3-g]isoquinoline-2-carboxamide(53B)

Using Compound 53A (3.9 mg) obtained above and according to the samemethod as Example 1, the title compound 53B was obtained (2.4 mg).

(53A) MS (ESI+) 337 (M⁺+1).

(53B) MS (ESI+) 307 (M⁺+1).

Reference Example 29 methyl2-(1,1-dimethoxyethyl)-4,9-dioxo-4,9-dihydrofuro[2,3-g]isoquinoline-3-carboxylate

A solution of 6,7-dichloroisoquinoline-5,8-dione (1.14 g), methyl4,4-dimethoxy-3-oxovalerate (1.05 g), and potassium carbonate (1.73 g)in acetonitrile (50 mL) was heated and stirred at 90° C. for 5 hours.After the heating was finished, the precipitated solid was filteredthrough Celite with ethyl acetate. After the filtrate was concentratedunder reduced pressure, the resulting residue was purified by silica gelcolumn chromatography (chloroform) to yield the title compound as ayellow solid (1.15 g).

MS (ESI+) 346 (M⁺+1).

Reference Example 30 methyl2-acetyl-4,9-dioxo-4,9-dihydrofuro[2,3-g]isoquinoline-3-carboxylate

A solution of Compound (1.15 g) (which was obtained in Reference example29) in formic acid (10 mL) was stirred at 25° C. for 4 hours. After thereaction solution was concentrated under reduced pressure, the resultingresidue was purified by silica gel column chromatography (chloroform) toyield the title compound as a yellow solid (0.87 g).

MS (ESI+) 300 (M⁺+1).

Example 472-acetyl-3-(morpholin-4-carbonyl)furo[2,3-g]isoquinoline-4,9-dione

A solution of the compound (0.5 g) (which was obtained in Referenceexample 29) in a mixture of 4 N hydrochloric acid in 1,4-dioxane (10 mL)and concentrated hydrochloric acid (4 mL) was stirred at 120° C. for 9hours. The reaction solution was concentrated under reduced pressure,and then a solution of DMF (10 mg) in toluene (5 mL) was added thereto.Subsequently, thionyl chloride (143 mg) was added dropwise, and thenheated and stirred at 90° C. for 4 hours. After the heating wasfinished, concentration under reduced pressure was performed. To theresidue, THF (5 mL) was added, and then morpholine (0.5 mL) was addeddropwise at 0° C. After stirring at 25° C. for 1 hour, concentrationunder reduced pressure was performed. The resulting residue was purifiedby silica gel column chromatography (chloroform) to yield the titlecompound as a yellow solid (70 mg).

MS (ESI+) 355 (M⁺+1).

Reference Example 31 4, 9-dimethoxyfuro[2,3-g]isoquinoline-3-carboxylicacid (54C)

(a) Methyl6-{[(2,2-dimethoxyethyl)amino]methyl}-4,7-dimethoxy-1-benzofuran-2-carboxylate(54A)

Using Compound 49B (605 mg) obtained in Reference example 26 andaccording to the same method as Reference example 10b, Compound 54A wasobtained as a crude product. The whole amount of this product was usedin the next reaction.

(b) Methyl6-({(2,2-dimethoxyethyl)[(2-nitrophenyl)sulfonyl]amino}methyl)-4,7-dimethoxy-1-benzofuran-2-carboxylate(54B)

Using the above-described crude product 54A and according to the samemethod as Reference example 10c, Compound 54B (1.10 g) was obtained.

(c) 4,9-Dimethoxyfuro[2,3-g]isoquinoline-3-carboxylic acid (54C)

Using Compound 54B (500 mg) obtained above and according to the samemethod as Reference example 10d, the title compound 54C was obtained(126 mg).

(54A) MS (ESI+) 354 (M⁺+1).

(54B) ¹H-NMR (DMSO-d₆, δ ppm): 8.02 (2H, d, J=7.9 Hz), 7.98 (2H, d,J=7.9 Hz), 7.85 (1H, t, J=7.6 Hz), 7.76 (1H, t, J=7.6 Hz), 7.62 (1H, s),6.52 (1H, s), 4.71 (2H, s), 4.38 (1H, t, J=4.9 Hz), 3.96 (3H, s), 3.88(3H, s), 3.70 (3H, s), 3.35 (2H, d, J=5.5 Hz), 3.17 (6H, s).

MS (ESI+) 539 (M⁺+1).

(54C) ¹H-NMR (DMSO-d₆, δ ppm): 14.05 (1H, br s), 9.57 (1H, s), 8.44 (1H,d, J=6.1 Hz), 8.08 (1H, s), 7.97 (1H, d, J=6.1 Hz), 4.27 (6H, s).

MS (ESI+) 274 (M⁺+1).

Reference Example 321-(4,9-dimethoxyfuro[3,2-g]isoquinolin-2-yl)ethanone (55B)

(a) (4,9-Dimethoxyfuro[3,2-g]isoquinolin-2-yl) (morpholin-4-yl)methanone(55A)

Using 4,9-dimethoxyfuro[2,3-g]isoquinoline-3-carboxylic acid obtained inReference example 31 and according to the same method as Referenceexample 6a, Compound 55A was obtained (80.0 mg).

(b) 1-(4,9-Dimethoxyfuro[3,2-g]isoquinolin-2-yl)ethanone (55B)

Using Compound 55A (80.0 mg) obtained above and according to the samemethod as Reference example 6b, the title compound 55B was obtained(27.0 mg).

(55A) ¹H-NMR (DMSO-d₆, δ ppm): 9.56 (1H, s), 8.44 (1H, d, J=6.1 Hz),7.95 (1H, d, J=6.1 Hz), 7.84 (1H, s), 4.29 (3H, s), 4.22 (3H, s),3.87-3.57 (8H, m).

MS (ESI+) 343 (M⁺+1).

(55B) ¹H-NMR (DMSO-d₆, δ ppm): 9.61 (1H, s), 8.55 (1H, d, J=6.1 Hz),8.36 (1H, s), 8.04 (1H, d, J=6.1 Hz), 4.19 (3H, s), 4.14 (3H, s), 3.94(3H, s).

MS (ESI+) 272 (M⁺+1).

Example 48 2-acetylfuro[3,2-g]isoquinoline-4,9-dione

Using Compound 55B (27.0 mg) of Reference example 32 and according tothe same method as Example 1, the title compound was obtained (15.0 mg).

MS (ESI+) 242 (M⁺+1).

Example 49 2-(1-hydroxyethyl)furo[3,2-g]isoquinoline-4,9-dione (56B)

(a) 1-(4,9-Dimethoxyfuro[3,2-g]isoquinolin-2-yl)ethanol (56A)

Using Compound 55B (60.0 mg) of Reference example 32 and according tothe same method as Reference example 2a, Compound 56A was obtained (24.0mg).

(b) 2-(1-Hydroxyethyl)furo[3,2-g]isoquinoline-4,9-dione (56B)

Using Compound 56A (24.0 mg) obtained above and according to the samemethod as Example 2b, the title compound 56B was obtained (15.0 mg).

(56A) MS (ESI+) 242 (M⁺+1).

(56B) ¹H-NMR (DMSO-d₆, δ ppm): 9.24 (1H, s), 9.10 (1H, br s), 7.92 (1H,br s), 6.95 (1H, br s), 5.83 (1H, d, J=5.5 Hz), 4.92-4.85 (1H, m), 1.46(3H, d, J=6.7 Hz).

MS (ESI+) 244 (M⁺+1).

Reference Example 33 1-(4,9-dimethoxyfuro[3,2-g]quinolin-2-yl)ethanol(57E)

(a) Methyl 4,9-dimethoxyfuro[3,2-g]quinoline-2-carboxylate (57A)

To a solution of methyl 6-amino-4,7-dimethoxybenzofuran-2-carboxylate(100 mg) (which was obtained in Reference example 21) in methanol (0.9mL) were added in concentrated hydrochloric acid (0.4 mL), and2-propenal (60 μL), and then the reaction mixture was stirred at 70° C.for 2 hours. After it was returned to room temperature, the solvent wasevaporated off to yield Compound 57A. The obtained compound was used inthe next reaction without purification.

(b) 4,9-Dimethoxyfuro[3,2-g]quinoline-2-carboxylic acid (57B)

Methyl 4,9-dimethoxyfuro[3,2-g]quinoline-2-carboxylate (which wasobtained above) was added to concentrated hydrochloric acid (1.0 mL),and then the reaction mixture was heated at reflux for 1 hour. After itwas returned to room temperature, the solvent was evaporated off toyield Compound 57B. The obtained compound was used in the next reactionwithout purification.

(c) (4,9-Dimethoxyfuro[3,2-g]quinolin-2-yl) (morpholin-4-yl)methanone(57C)

Using 4,9-dimethoxyfuro[3,2-g]quinoline-2-carboxylic acid obtained aboveand according to the same method as Reference example 6a, Compound 57Cwas obtained (53.0 mg).

(d) 1-(4,9-Dimethoxyfuro[3,2-g]quinolin-2-yl)ethanone (57D)

Using (4,9-dimethoxyfuro[3,2-g]quinolin-2-yl) (morpholin-4-yl)methanone(53 mg) obtained above and according to the same method as Referenceexample 6b, Compound 57D was obtained.

(e) 1-(4,9-Dimethoxyfuro[3,2-g]quinolin-2-yl)ethanol (57E)

Using 1-(4,9-dimethoxyfuro[3,2-g]quinolin-2-yl)ethanone (10 mg) obtainedabove and according to the same method as Example 2a, the title compound57E was obtained.

(57A) MS (ESI+) 288 (M⁺+1).

(57B) MS (ESI+) 274 (M⁺+1).

(57C) MS (ESI+) 343 (M⁺+1).

(57D) MS (ESI+) 272 (M⁺+1).

(57E) MS (ESI+) 274 (M⁺+1).

Example 50 2-acetylfuro[3,2-g]quinoline-4,9-dione

Using 1-(4,9-dimethoxyfuro[3,2-g]quinolin-2-yl)ethanone (35 mg) obtainedin Reference example 33 and according to the same method as Example 1,the title compound was obtained (7.1 mg).

MS (ESI+) 242 (M⁺+1).

Example 51 2-(1-hydroxyethyl)furo[3,2-g]quinoline-4,9-dione

Using 1-(4,9-dimethoxyfuro[3,2-g]quinolin-2-yl)ethanol obtained inReference example 33 and according to the same method as Example 1, thetitle compound was obtained (3.7 mg).

MS (ESI+) 244 (M⁺+1).

Reference Example 34 (4,7-dimethoxy-1-benzofuran-2-yl)(morpholin-4-yl)methanone (58B)

(a) 4,7-Dimethoxy-1-benzofuran-2-carboxylic acid (58A)

Using methyl 4,7-dimethoxy-1-benzofuran-2-carboxylate (16.0 g) obtainedin Reference example 19 and according to the same method as Referenceexample 5, Compound 58A (7.2 g) was obtained.

(b) (4,7-Dimethoxy-1-benzofuran-2-yl) (morpholin-4-yl)methanone (58B)

Using Compound 58A (7.2 g) obtained above and according to the samemethod as Reference example 6a, the title compound 58B was obtained as ayellow powder (9.8 g).

(58A) MS (ESI+) 223 (M⁺+1).

(58B) MS (ESI+) 292 (M⁺+1).

Reference Example 354,7-dimethoxy-2-(morpholin-4-ylcarbonyl)-1-benzofuran-5-carbaldehyde(59A) Reference Example 364,7-dimethoxy-2-(morpholin-4-ylcarbonyl)-1-benzofuran-6-carbaldehyde(59B)

Using (4,7-dimethoxy-1-benzofuran-2-yl) (morpholin-4-yl)methanone (9.8g) under nitrogen atmosphere and according to the same methods asReference examples 25 and 26, Compound 59A (8.8 g) and Compound 59B(0.88 g) were obtained as yellow solids, respectively.

(59A) MS (ESI+) 320 (M⁺+1).

(59B) MS (ESI+) 320 (M⁺+1).

Reference Example 371-(4,8-dimethoxythieno[3,2-f][1]benzofuran-2-yl)ethanone (60E)

(a)4,7-Dimethoxy-2-(morpholin-4-ylcarbonyl)-6-nitro-1-benzofuran-5-carbaldehyde(60A)

To a solution of4,7-dimethoxy-2-(morpholin-4-ylcarbonyl)-1-benzofuran-5-carbaldehyde(8.8 g) (which was obtained in Reference example 35) in acetic acid (50mL) was added dropwise 70% aqueous nitric acid solution (12.3 mL), andthen the reaction mixture was heated and stirred at 70° C. for 1.5hours. After the reaction solution was cooled to room temperature, itwas poured into iced water, and then extracted with ethyl acetate twotimes. The resulting organic layer was washed with water and saturatedbrine, and then dried over sodium sulfate. The solvent was thenevaporated off. The resulting residue was purified by silica gelchromatography (ethyl acetate/chloroform) to yield Compound 60A (7.09 g)as a yellow solid.

(b) Methyl4,8-dimethoxy-2-(morpholin-4-ylcarbonyl)thieno[3,2-f][1]benzofuran-6-carboxylate(60B)

Using Compound 60A (7.09 g) obtained above and according to the samemethod as Reference example 1, Compound 60B (4.06 g) was obtained as ayellow solid.

(c)4,8-Dimethoxy-2-(morpholin-4-ylcarbonyl)thieno[3,2-f][1]benzofuran-6-carboxylicacid (60C)

Using Compound 60B (4.06 g) obtained above and according to the samemethod as Reference example 5, Compound 60C (3.5 g) was obtained.

(d) (4,8-Dimethoxythieno[3,2-f][1]benzofuran-2-yl)(morpholin-4-yl)methanone (60D)

To a solution of Compound 60C (3.50 g) (which was obtained above) inquinoline (10 mL) was added copper (3.40 g), and then the reactionmixture was stirred at 190° C. for 5 hours. After the reaction solutionwas cooled to room temperature, it was poured into iced water,neutralized to pH=3-5 with 1 N aqueous hydrochloric acid solution, andthen extracted with ethyl acetate. The resulting organic layer waswashed with water and saturated brine, and then dried over sodiumsulfate. The solvent was then evaporated off. The resulting residue waspurified by silica gel chromatography (ethyl acetate/chloroform) toyield Compound 60D (670 mg) as a yellow solid.

(e) 1-(4,8-Dimethoxythieno[3,2-f][1]benzofuran-2-yl)ethanone (60E)

Using Compound 60D (580 mg) obtained above and according to the samemethod as Reference example 6b, the title compound 60E was obtained as ayellow powder (350 mg).

(60A) MS (ESI+) 365 (M⁺+1).

(60B) MS (ESI+) 406 (M⁺+1).

(60C) MS (ESI+) 392 (M⁺+1).

(60D) MS (ESI+) 348 (M⁺+1).

(60E) MS (ESI+) 277 (M⁺+1).

Example 52 2-acetylthieno[3,2-f][1]benzofuran-4,8-dione

Using 1-(4,8-dimethoxythieno[3,2-f][1]benzofuran-2-yl)ethanone (300 mg)obtained in Reference example 37 and according to the same method asExample 1, the title compound was obtained as a yellow powder (260 mg).

MS (ESI+) 247 (M⁺+1).

Example 53 2-(1-hydroxyethyl)thieno[3,2-f][1]benzofuran-4,8-dione (61B)

(a) 1-(4,8-Dimethoxythieno[3,2-f][1]benzofuran-2-yl)ethanol (61A)

Using 1-(4,8-dimethoxythieno[3,2-f][1]benzofuran-2-yl)ethanone (50 mg)obtained in Reference example 37 and according to the same method asExample 2a, Compound 61A was obtained as a yellow solid (50 mg).

(b) 2-(1-Hydroxyethyl)thieno[3,2-f][1]benzofuran-4,8-dione (61B)

Using Compound 61A (50 mg) obtained above and according to the samemethod as Example 1, the title compound 61B was obtained as a yellowpowder (33 mg).

(61A) MS (ESI+) 279 (M⁺+1).

(61B) MS (ESI+) 249 (M⁺+1).

Example 54 2-(2-hydroxypropan-2-yl)thieno[3,2-f][1]benzofuran-4,8-dione(62B)

(a) 2-(4,8-Dimethoxythieno[3,2-f][1]benzofuran-2-yl)propan-2-ol (62A)

Using 1-(4,8-dimethoxythieno[3,2-f][1]benzofuran-2-yl)ethanone (50 mg)obtained in Reference example 37 and according to the same method asExample 15a, Compound 62A was obtained as a yellow solid (49 mg).

(b) 2-(2-Hydroxypropan-2-yl)thieno[3,2-f][1]benzofuran-4,8-dione (62B)

Using Compound 62A (50 mg) obtained above and according to the samemethod as Example 1, the title compound 62B was obtained as a yellowpowder (33 mg).

(62A) MS (ESI+) 293 (M⁺+1).

(62B) MS (ESI+) 263 (M⁺+1).

Example 552-(morpholin-4-ylcarbonyl)thieno[3,2-f][1]benzofuran-4,8-dione

Using (4,8-dimethoxythieno[3,2-f][1]benzofuran-2-yl)(morpholin-4-yl)methanone (84 mg) obtained in Reference example 37d andaccording to the same method as Example 1, the title compound wasobtained as a yellow powder (66 mg).

MS (ESI+) 318 (M⁺+1).

Example 56 2-acetylthieno[2,3-f][1]benzofuran-4,8-dione (63F)

(a)4,7-Dimethoxy-2-(morpholin-4-ylcarbonyl)-5-nitro-1-benzofuran-6-carbaldehyde(63A)

Using4,7-dimethoxy-2-(morpholin-4-ylcarbonyl)-1-benzofuran-6-carbaldehyde(880 mg) obtained in Reference example 36 and according to the samemethod as Reference example 37a, Compound 63A was obtained as a yellowpowder (840 mg).

(b) Methyl4,8-dimethoxy-2-(morpholin-4-ylcarbonyl)thieno[2,3-f][1]benzofuran-6-carboxylate(63B)

Using Compound 63A (840 mg) obtained above and according to the samemethod as Reference example 37b, Compound 63B was obtained as a yellowpowder (460 mg).

(c)4,8-Dimethoxy-2-(morpholin-4-ylcarbonyl)thieno[2,3-f][1]benzofuran-6-carboxylicacid (63C)

Using Compound 63B (460 mg) obtained above and according to the samemethod as Reference example 37c, Compound 63C was obtained as a yellowpowder (190 mg).

(d) (4,8-Dimethoxythieno[2,3-f][1]benzofuran-2-yl)(morpholin-4-yl)methanone (63D)

Using Compound 63C (190 mg) obtained above and according to the samemethod as Reference example 37d, Compound 63D was obtained as a yellowpowder (80 mg).

(e) 1-(4,8-Dimethoxythieno[2,3-f][1]benzofuran-2-yl)ethanone (63E)

Using Compound 63D (80 mg) obtained above and according to the samemethod as Reference example 37e, Compound 63E was obtained as a yellowpowder (47 mg).

(f) 2-Acetylthieno[2,3-f][1]benzofuran-4,8-dione (63F)

Using Compound 63E (47 mg) obtained above and according to the samemethod as Example 1, the title compound 63F was obtained as a yellowpowder (19 mg).

(63A) MS (ESI+) 365 (M⁺+1).

(63B) MS (ESI+) 406 (M⁺+1).

(63C) MS (ESI+) 392 (M⁺+1).

(63D) MS (ESI+) 348 (M⁺+1).

(63E) MS (ESI+) 277 (M⁺+1).

(63F) MS (ESI+) 247 (M⁺+1).

Reference Example 38 dimethyl4,8-dioxo-4,8-dihydrothieno[3,2-f][1]benzofuran-2,6-dicarboxylate (64C)

(a) Methyl 5-formyl-4,7-dimethoxy-6-nitro-1-benzofuran-2-carboxylate(64A)

Using methyl 5-formyl-4,7-dimethoxy-1-benzofuran-2-carboxylate (33 mg)obtained in Reference example 25 and according to the same method asReference example 37a, Compound 64A was obtained as a yellow powder (21mg).

(b) Dimethyl 4,8-dimethoxythieno[3,2-f][1]benzofuran-2,6-dicarboxylate(64B)

Using Compound 64A (21 mg) obtained above and according to the samemethod as Reference example 37b, Compound 64B was obtained as a yellowpowder (11 mg).

(c) Dimethyl4,8-dioxo-4,8-dihydrothieno[3,2-f][1]benzofuran-2,6-dicarboxylate (64C)

Using Compound 64B (11 mg) obtained above and according to the samemethod as Example 1, the title compound 64C was obtained as a yellowpowder (4 mg).

(64A) MS (ESI+) 310 (M⁺+1).

(64B) MS (ESI+) 351 (M⁺+1).

(64C) MS (ESI+) 321 (M⁺+1).

Reference Example 39 5, 9-dimethoxythieno[2,3-g]quinoxaline-7-carboxylicacid (65D)

(a) Methyl 4,7-dimethoxy-5,6-dinitro-1-benzothiophene-2-carboxylate(65A)

A solution of methyl 4,7-dimethoxy-1-benzothiophene-2-carboxylate (3.70g) (which was obtained in Reference example 1) in aqueous nitric acidsolution (37 mL) was stirred for 1.5 hours under heating at reflux.After it was returned to room temperature, the reaction solution waspoured into iced water, and then extracted with ethyl acetate two times.The resulting organic layer was washed with aqueous saturated sodiumbicarbonate and saturated brine, and then dried over sodium sulfate. Thesolvent was then evaporated off to yield Compound 65A as a yellow powder(5.05 g).

(b) Methyl 5,6-diamino-4,7-dimethoxy-1-benzothiophene-2-carboxylate(65B)

To a solution of Compound 65A (5.05 g) (which was obtained above) inmethanol (50 mL), under ice-cooling, were slowly added nickel chloride(1.90 g), sodium borohydride (2.77 g), and then the reaction mixture wasstirred at 0° C. for 1.5 hours. The reaction solution was returned toroom temperature, and then filtered through Celite. The solvent of thefiltrate was then evaporated off. The resulting residue was dissolved inethyl acetate, washed with aqueous saturated sodium bicarbonate andsaturated brine, and then dried over sodium sulfate. The solvent wasthen evaporated off to yield Compound 65B as a brown solid (0.64 g).

(c) Methyl 5, 9-dimethoxythieno[2,3-g]quinoxaline-7-carboxylate (65C)

To a solution of Compound 65B (640 mg) (which was obtained above) in THF(68.0 mL) was added 40% aqueous glyoxal solution (2.27 mL), and then thereaction mixture was stirred for 1 hour under heating at reflux. Thereaction solution was returned to room temperature, and then the solventwas evaporated off. The resulting residue was dissolved in chloroform,washed with water and saturated brine, and then dried over sodiumsulfate. The solvent was then evaporated off to yield Compound 65C as ayellow powder (679 mg).

(d) 5,9-Dimethoxythieno[2,3-g]quinoxaline-7-carboxylic acid (65D)

Using Compound 65C (679 mg) obtained above and according to the samemethod as Reference example 5, the title compound 65D was obtained as ayellow solid.

(65A) ¹H-NMR (DMSO-d₆, δ ppm): 8.51 (1H, s), 4.16 (3H, s), 4.15 (3H, s),3.97 (3H, s).

(65B) ¹H-NMR (CDCl₃, δ ppm): 8.04 (1H, s), 3.94 (3H, s), 3.93 (3H, s),3.92 (3H, s).

MS (ESI+) 283 (M⁺+1).

(65C) ¹H-NMR (DMSO-d₆, δ ppm): 9.01-8.99 (2H, m), 8.33 (1H, s), 4.30(3H, s), 4.27 (3H, s), 3.94 (3H, s).

MS (ESI+) 305 (M⁺+1).

(65D) MS (ESI+) 291 (M⁺+1).

Example 57 7-(morpholin-4-ylcarbonyl)thieno[2,3-g]quinoxaline-5,9-dione(66B)

(a) 5,9-Dimethoxythieno[2,3-g]quinoxalin-7-yl(morpholin-4-yl)methanone(66A)

Using 5,9-dimethoxythieno[2,3-g]quinoxaline-7-carboxylic acid (64.7 mg)obtained in Reference example 39 and according to the same method asReference example 6a, Compound 66A was obtained as a brown solid (98.7mg).

(b) 7-(Morpholin-4-ylcarbonyl)thieno[2,3-g]quinoxaline-5,9-dione (66B)

Using Compound 66A (15.0 mg) obtained above and according to the samemethod as Example 1, the title compound 66B was obtained as a yellowsolid (2.5 mg).

(66A) ¹H-NMR (DMSO-d₆, δ ppm): 8.98 (2H, s), 7.92 (1H, s), 4.26 (3H, s),4.25 (3H, s), 3.80-3.63 (8H, m).

MS (ESI+) 360 (M⁺+1).

(66B) MS (ESI+) 330 (M⁺+1).

Example 587-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]carbonyl}thieno[2,3-g]quinoxaline-5,9-dione(67B)

(a)5,9-Dimethoxythieno[2,3-g]quinoxalin-7-yl)[(2R,6S)-2,6-dimethylmorpholin-4-yl]methanone(67A)

Using 5,9-dimethoxythieno[2,3-g]quinoxaline-7-carboxylic acid (which wasobtained in Reference example 39) and (2S,6R)-2,6-dimethylmorpholine(51.4 mg) and according to the same method as Reference example 6a,Compound 67A was obtained as a brown solid (82.4 mg).

(b)7-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]carbonyl}thieno[2,3-g]quinoxaline-5,9-dione(67B)

Using Compound 67A (16.5 mg) obtained above and according to the samemethod as Example 1, the title compound 67B was obtained as a yellowsolid (9.7 mg).

(67A) MS (ESI+) 388 (M⁺+1).

(67B) MS (ESI+) 358 (M⁺+1).

Reference Example 40 5,9-dimethoxy-7-(morpholin-4-ylmethyl)thieno[2,3-g]quinoxaline (68C)

(a) (5,9-Dimethoxythieno[2,3-g]quinoxalin-7-yl)methanol (68A)

Using 5,9-dimethoxythieno[2,3-g]quinoxaline-7-carboxylic acid (31.4 mg)obtained in Reference example 39 and according to the same method asReference example 12, Compound 68A was obtained as a yellow powder (9.0mg).

(b) 7-(Chloromethyl)-5,9-dimethoxythieno[2,3-g]quinoxaline (68B)

Using Compound 68A (7.0 mg) obtained above and according to the samemethod as Reference example 7b, Compound 68B was obtained as a yellowsolid.

(c) 5,9-Dimethoxy-7-(morpholin-4-ylmethyl)thieno[2,3-g]quinoxaline (68C)

Using Compound 68B obtained above and according to the same method asReference example 8, the title compound 68C was obtained as a yellowpowder (4.4 mg).

(68A) ¹H-NMR (DMSO-d₆, δ ppm): 8.95-8.92 (2H, m), 7.54 (1H, s), 5.84(1H, t, J=6.0 Hz), 4.81 (2H, d, J=6.0 Hz), 4.23 (3H, s), 4.18 (3H, s).

MS (ESI+) 277 (M⁺+1).

(68B) ¹H-NMR (DMSO-d₆, δ ppm): 9.00-8.91 (2H, m), 7.82 (1H, s), 5.21(2H, s), 4.22 (3H, s), 4.18 (3H, s).

MS (ESI+) 295 (M⁺+1).

(68C) MS (ESI+) 346 (M⁺+1).

Example 59 7-(morpholin-4-ylmethyl)thieno[2,3-g]quinoxaline-5,9-dione

Using 5, 9-dimethoxy-7-(morpholin-4-ylmethyl)thieno[2,3-g]quinoxaline(4.0 mg) obtained in Reference example 40 and according to the samemethod as Example 1, the title compound was obtained as a yellow solid(0.6 mg).

¹H-NMR (CDCl₃, δ ppm): 8.98-8.96 (2H, m), 7.59 (1H, s), 3.90-3.50 (6H,m), 2.70-2.40 (4H, m).

MS (ESI+) 316 (M⁺+1).

Reference Example 41 methyl2-(1,1-dimethoxyethyl)-4,9-dioxo-4,9-dihydrofuro[2,3-g]phthalazine-3-carboxylate

Using 6,7-dichlorophthalazine-5,8-dione (1.14 g) and according to thesame method as Reference example 29, the title compound was obtained asa yellow solid (0.1 g).

MS (ESI+) 341 (M⁺+1).

Reference Example 42 methyl2-acetyl-4,9-dioxo-4,9-dihydrofuro[2,3-g]phthalazine-3-carboxylate

Using the compound (0.1 g) obtained in Reference example 41 andaccording to the same method as Reference example 30, the title compoundwas obtained as a yellow solid (0.03 g).

MS (ESI+) 301 (M⁺+1).

Reference Example 434,9-dimethoxythieno[2,3-g]isoquinoline-2-carbaldehyde

To a solution of (4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)methanol(315 mg) (which was obtained in Reference example 12) in dichloromethane(30 mL) was added manganese dioxide (1.6 g) under room temperature, andthen the reaction mixture was stirred for 12 hours. The reactionsolution was filtered through Celite, and then the solvent of thefiltrate was evaporated off. The resulting residue was purified bysilica gel column chromatography (chloroform/methanol) to yield thetitle compound (169 mg).

LC-MS: [M+H]⁺/Rt(min)=274/0.39.

Reference Example 44 ethyl(E)-3-(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)acrylate

To a solution of 4,9-dimethoxythieno[2,3-g]isoquinoline-2-carbaldehyde(86 mg) (which was obtained in Reference example 43) in toluene (30 mL)was added (carbethoxymethylene)triphenylphosphorane (164 mg) under roomtemperature, and then the reaction mixture was stirred at 80° C. for 2hours. The reaction solution was cooled to room temperature, and thenthe solvent of the filtrate was evaporated off. The resulting residuewas purified by silica gel column chromatography (chloroform/ethylacetate) to yield the title compound (68 mg).

LC-MS: [M+H]⁺/Rt(min)=344/0.87.

Example 60 ethyl(E)-3-(4,9-dioxo-4,9-dihydrothieno[2,3-g]isoquinolin-2-yl)acrylate

Using ethyl (E)-3-(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)acrylate(68 mg) obtained in Reference example 44 and according to the samemethod as Example 1, the title compound was obtained as a yellow powder(24 mg).

LC-MS: [M+H]⁺/Rt(min)=314/0.97.

Reference Example 45 2-ethynyl-4,9-dimethoxythieno[2,3-g]isoquinoline

To a solution of 4,9-dimethoxythieno[2,3-g]isoquinoline-2-carbaldehyde(83 mg) (which was obtained in Reference example 43) in methanol (30 mL)was added potassium carbonate (126 mg) anddimethyl(1-diazo-2-oxopropyl)phosphonate (88 mg) under room temperature,and then the reaction mixture was stirred at 0° C. for 5 hours. Thereaction solution was returned to room temperature, and then filtratedthrough Celite. The solvent of the filtrate was then evaporated off. Theresulting residue was purified by silica gel column chromatography(chloroform/ethyl acetate) to yield the title compound (32 mg).

LC-MS: [M+H]⁺/Rt(min)=270/0.76.

Example 61 2-ethynylthieno[2,3-g]isoquinoline-4,9-dione

Using 2-ethynyl-4,9-dimethoxythieno[2,3-g]isoquinoline (32 mg) obtainedin Reference example 45 and according to the same method as Example 1,the title compound was obtained as a yellow powder (9 mg).

LC-MS: [M+H]⁺/Rt(min)=240/0.87.

Reference Example 46 ethyl2-(difluoromethyl)-4,9-dioxo-4,9-dihydrofuro[2,3-g]isoquinoline-3-carboxylate

A solution of 6,7-dichloroisoquinoline-5,8-dione (355 mg), ethyl4,4-difluoroacetoacetate (288 μL), potassium carbonate (507 mg) inacetonitrile (15 mL) was stirred for 5 hours under heating at reflux.The reaction solution was cooled to room temperature. The insolublesubstance was filtered and then the filtrate was concentrated underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate) to yield the title compoundas a yellow solid (225 mg).

MS (ESI+) 322 (M⁺+1).

Reference Example 472-(difluoromethyl)-4,9-dioxo-4,9-dihydrofuro[2,3-g]isoquinoline-3-carboxylicacid

A solution of ethyl2-(difluoromethyl)-4,9-dioxo-4,9-dihydrofuro[2,3-g]isoquinoline-3-carboxylate(190 mg) (which was obtained in Reference example 46) in concentratedhydrochloric acid (20 mL) was stirred for 2 hours under heating atreflux. The reaction solution was cooled to room temperature and thenconcentrated under reduced pressure to yield a crude product of thetitle compound (176 mg).

MS (ESI+) 294 (M⁺+1).

Example 622-(difluoromethyl)-3-(morpholine-4-carbonyl)furo[2,3-g]isoquinoline-4,9-dione

DMF (10 μL) was added to a solution of2-(difluoromethyl)-4,9-dioxo-4,9-dihydrofuro[2,3-g]isoquinoline-3-carboxylicacid (158 mg) (which was obtained in Reference example 47) in thionylchloride (5 mL), and then the reaction mixture was stirred at 100° C.for 5 hours. The reaction solution was cooled to room temperature andthen concentrated under reduced pressure. The resulting residue was thendissolved in THF (5 mL) and cooled to 0° C. Subsequently, morpholine (94μL) was added dropwise, and then the reaction solution was stirred atroom temperature for 15 minutes. The reaction solution was concentratedunder reduced pressure, and then water and chloroform were added to theresidue, followed by extraction with chloroform. The organic layer wasdried over anhydrous sodium sulfate and then filtered. The filtrate wasconcentrated under reduced pressure, and then the resulting residue waspurified by silica gel column chromatography (hexane/ethyl acetate) toyield the title compound as a yellow solid (41 mg).

MS (ESI+) 363 (M⁺+1).

Example 63 2-(difluoromethyl)furo[2,3-g]isoquinoline-4,9-dione

To a solution of2-(difluoromethyl)-4,9-dioxo-4,9-dihydrofuro[2,3-g]isoquinoline-3-carboxylicacid (211 mg) (which was obtained in Reference example 47) in quinoline(3 mL) was added cupper powder (133 mg), and then the reaction mixturewas stirred at 150° C. for 1 hour. The reaction solution was cooled toroom temperature, poured into iced water, and then extracted withchloroform. The organic layer was dried over anhydrous sodium sulfate,filtered, and then concentrated under reduced pressure. The organiclayer was dried over anhydrous sodium sulfate, and then filtered. Thefiltrate was concentrated under reduced pressure, and then the resultingresidue was purified by silica gel column chromatography (hexane/ethylacetate) to yield the title compound as a yellow solid (72 mg).

LC-MS: [M+H]⁺/Rt(min)=250/0.75.

Test Example 1 Proliferation Inhibition Assay of Cancer Cells

HCT-116 cells (derived from human colon adenocarcinoma), HT-29 cells(derived from human colon cancer), and FaDu cells (derived from humanhypopharynx cancer) were obtained from American Type Culture Collection(ATCC). HCT-116 cells and HT-29 cells were cultured using McCoy's 5amedium containing 10% fetal bovine serum (FBS) and 1%penicillin/streptomycin, and FaDu cells were cultured using MEM mediumcontaining 10% FBS, 1% non-essential amino acid, 1% sodium pyruvate, and1% penicillin/streptomycin, respectively, at 37° C. in the presence of5% CO₂. After cells were seeded at 300-600 cells/well onto blackμClear-plate 384 well (Greiner bio-one Cat. No. 781091), a testsubstance was added such that the final concentration of DMSO is 0.1%,and cultured for 4 days. The number of living cells was then countedusing Cell Titer-Glo (Registered trademark) Luminescent Cell ViabilityAssay (Promega) to calculate a concentration for 50% inhibition of cellproliferation of respective test substances (Bulk 1050 value; μM).

A test shown in Test example 1 was carried out for compounds obtained inthe Examples.

The concentrations for 50% inhibition of cell proliferation ofrespective test substances (Bulk 1050 value; μM) are shown in Table 1.

TABLE 1 IC₅₀ (μM) Example HCT FaDu HT 1 0.01 0.01 0.57 2 0.08 0.10 0.863 0.06 0.07 0.56 4 0.57 0.46 0.68 5 0.45 0.54 0.92 6 0.39 0.41 0.93 70.40 0.40 2.64 8 0.38 0.37 0.83 9 0.53 0.60 >10 10 0.50 0.50 6.14 110.49 0.45 3.85 12 0.05 <0.01 0.18 13 0.06 0.02 0.37 14 0.06 0.03 0.48 150.34 0.04 0.61 16 0.06 <0.01 0.58 17 0.41 0.84 0.87 18 1.00 0.57 >10 190.07 <0.01 0.10 20 0.05 <0.01 0.09 21 0.06 <0.01 0.07 22 0.48 0.44 0.8123 0.10 0.03 0.58 24 0.34 0.03 0.65 25 0.69 0.46 0.96 26 0.09 0.02 0.4527 0.50 0.03 0.40 28 0.47 0.08 0.63 29 0.04 <0.01 0.32 30 <0.01 <0.010.05 31 0.04 <0.01 0.31 32 6.56 2.15 >10 33 <0.01 <0.01 0.09 34 0.070.04 0.64 35 0.08 0.05 0.60 36 0.10 0.09 0.73 37 0.06 0.08 0.62 38 0.550.44 0.66 39 0.38 0.09 3.71 40 0.07 0.05 0.55 41 0.70 0.78 4.52 42 0.540.47 0.72 43 0.62 0.66 5.62 44 0.06 0.03 0.51 45 0.06 0.03 0.52 46 <0.01<0.01 0.05 47 0.36 0.05 0.41 48 0.07 0.06 0.62 49 0.04 <0.01 0.08 500.47 0.47 0.59 51 0.39 0.49 0.84 52 0.07 0.43 0.64 53 0.55 0.64 0.68 540.61 0.67 2.47 55 0.05 0.06 0.58 56 0.09 0.56 0.62 57 5.71 8.21 >10 580.64 3.71 7.06 59 0.28 0.36 0.84 60 2.71 0.75 >10 61 0.19 0.05 0.54 620.06 0.04 0.57 63 0.05 0.05 0.54

As shown in Table 1, the compounds of the present invention exhibitedstrong inhibitory effects on the proliferation of cancer cells in theproliferation inhibition test of cancer cells. The compounds of Examples1, 12, 16, 19, 20, 21, 29, 30, 31, 33, 46, 49, 62, and 63 exhibited aparticularly strong effect on the inhibition of the proliferation ofcancer cells.

Test Example 2 Inhibition Assay of Cancer Cell Sphere-Forming Ability

HCT-116 cells (derived from human colon adenocarcinoma), HT-29 cells(derived from human colon cancer), FaDu cells (derived from humanhypopharynx cancer) were obtained from American Type Culture Collection(ATCC). HCT-116 cells and HT-29 cells were cultured using McCoy's 5amedium containing 10% fetal bovine serum (FBS) and 1%penicillin/streptomycin, and FaDu cells were cultured using MEM mediumcontaining 10% FBS, 1% non-essential amino acid, 1% sodium pyruvate, and1% penicillin/streptomycin, respectively, at 37° C. in the presence of5% CO₂. HCT-116 cells, HT-29 cells, and FaDu cells were seeded onto 384Well Black Clear Bottom Ultra-Low Attachment Microplate (Corning Cat.No. 3827) using DMEM/F12 medium containing 2% B27 supplement (GIBCO), 20ng/mL epidermal growth factor (EGF) (peprotech), 10 ng/mL basicfibroblast growth factor (bFGF) (peprotech), 5 μg/mL insulin (Sigma),and 1% penicillin/streptomycin to be 350-800 cells/well. A testsubstance was added so that the final concentration of DMSO is 0.1%, andthen cultured for 4 days. The number of living cells was then countedusing Cell Titer-Glo (registered trademark) Luminescent Cell ViabilityAssay (Promega) to calculate the concentration for 50% inhibition ofcell proliferation of respective test substances (Sphere IC50 value;μM).

A test shown in Test example 2 was carried out for compounds obtained inthe Examples.

The concentrations for 50% inhibition of cell proliferation ofrespective test substances (Sphere IC50 value; μM) are shown in Table 2.

TABLE 2 IC₅₀ (μM) Example HCT FaDu HT 1 0.02 0.02 0.07 2 0.23 0.12 0.553 0.05 0.05 0.43 4 0.55 0.34 0.63 5 0.39 0.50 0.57 6 0.20 0.33 0.63 70.51 0.36 3.04 8 0.41 0.32 0.60 9 0.28 0.10 0.61 10 0.38 0.09 0.53 110.46 0.28 0.71 12 0.04 <0.01 0.03 13 0.05 <0.01 0.06 14 0.09 0.02 0.0915 0.40 <0.01 0.46 16 0.22 <0.01 0.15 17 0.55 0.05 0.54 18 5.71 0.63 >1019 0.05 <0.01 0.04 20 0.06 <0.01 0.06 21 0.05 <0.01 0.06 22 0.50 0.310.16 23 0.31 0.04 0.48 24 0.43 <0.01 0.18 25 0.80 0.06 <0.01 26 0.17<0.01 0.07 27 0.47 <0.01 0.06 28 0.57 0.09 0.59 29 0.05 <0.01 0.05 30<0.01 <0.01 <0.01 31 0.03 <0.01 <0.01 32 7.70 1.25 >10 33 0.02 <0.010.07 34 0.24 0.04 0.50 35 0.27 0.04 0.39 36 0.07 0.05 0.25 37 0.06 0.060.49 38 0.55 0.28 0.59 39 0.35 0.45 0.55 40 0.08 0.05 0.51 41 0.83 0.463.82 42 0.31 0.08 0.59 43 0.51 0.33 0.60 44 0.06 0.04 0.08 45 0.06 0.030.08 46 0.04 <0.01 0.05 47 0.26 0.05 0.17 48 0.07 0.05 0.55 49 0.04<0.01 0.06 50 0.26 0.17 0.58 51 0.09 0.08 0.43 52 0.05 0.06 0.08 53 0.560.45 0.59 54 0.60 0.59 0.77 55 0.04 0.01 0.04 56 0.06 0.08 0.58 57 4.975.65 >10 58 0.56 0.76 5.97 59 0.05 0.06 0.63 60 7.41 0.83 8.98 61 0.280.05 0.24 62 0.05 <0.01 0.04 63 0.06 0.04 0.24

As shown in Table 2, the compounds of the present invention exhibitedstrong effect to inhibit cancer cell sphere-forming ability in theinhibition test of cancer cell sphere-forming ability. The compounds ofExamples 12, 13, 15, 16, 19, 20, 21, 24, 26, 27, 29, 30, 31, 33, 46, 49,55, 62, and 63 exhibited a particularly strong effect to inhibit cancercell sphere-forming ability.

As described above, the present invention is illustrated by preferableembodiments of the present invention. However, it will be understoodthat the scope of the present invention should be interpreted only bythe claims. It will be understood that the contents of patents, patentapplications, and literatures cited in the present specification shouldbe incorporated by reference to the present specification as if theircontents per se are specifically described in the present specification.The present application claims priority to Japanese Patent ApplicationNo. 2014-72398 (filed on Mar. 31, 2014) and its contents areincorporated in the present application by reference in its entirety.

INDUSTRIAL APPLICABILITY

The present invention provides novel tricyclic quinone derivatives, orpharmacologically acceptable salts thereof, production methods and usesthereof. The tricyclic quinone derivatives of the present invention havestrong inhibitory effect on the proliferation of cancer cells and cancercell sphere-forming ability, and are useful in the prevention,treatment, and/or the like of a disease such as cancer and the like.

1. A compound represented by formula (1) or a pharmacologicallyacceptable salt thereof:

wherein A is O, S, or N—R⁶; the ring G is a 5- or 6-membered aromaticring that contains one to three heteroatoms consisting of O, S, and N asconstituent atoms; R¹ is each independently a hydrogen atom, a halogenatom, a cyano group, an optionally substituted 3- to 8-membered cyclicamino group, an optionally substituted C₁₋₆ alkyl group, with theproviso that an unsubstituted methyl group and a C₁₋₆ alkyl groupsubstituted with one dimethyl amino group or one chlorine atom areexcluded, an optionally substituted C₃₋₁₀ cycloalkyl group, anoptionally substituted C₁₋₆ alkenyl group, an optionally substitutedC₁₋₆ alkynyl group, an optionally substituted C₆₋₁₀ aryl group, anoptionally substituted 5- to 12-membered monocyclic or polycyclicheterocyclic group, an optionally substituted C₁₋₆ alkylcarbonyl group,an optionally substituted C₃₋₁₀ cycloalkylcarbonyl group, an optionallysubstituted C₆₋₁₀ arylcarbonyl group, an optionally substituted 5- to12-membered monocyclic or polycyclic heterocyclylcarbonyl group, acarboxyl group, an optionally substituted C₃₋₁₀ cycloalkyloxycarbonylgroup, an optionally substituted C₆₋₁₀ aryloxycarbonyl group, anoptionally substituted 5- to 12-membered monocyclic or polycyclicheterocyclyloxycarbonyl group, an optionally substituted aminocarbonylgroup, an optionally substituted 3- to 8-membered cyclic aminocarbonylgroup, an optionally substituted C₁₋₆ alkylthio group, an optionallysubstituted C₃₋₁₀ cycloalkylthio group, an optionally substituted C₆₋₁₀arylthio group, an optionally substituted 5- to 12-membered monocyclicor polycyclic heterocyclylthio group, a sulfinate group, an optionallysubstituted C₁₋₆ alkylsulfinyl group, an optionally substituted C₃₋₁₀cycloalkylsulfinyl group, an optionally substituted C₆₋₁₀ arylsulfinylgroup, an optionally substituted 5- to 12-membered monocyclic orpolycyclic heterocyclylsulfinyl group, an optionally substitutedaminosulfinyl group, an optionally substituted 3- to 8-membered cyclicaminosulfinyl group, a sulfonate group, an optionally substituted C₁₋₆alkylsulfonyl group, an optionally substituted C₃₋₁₀ cycloalkylsulfonylgroup, an optionally substituted C₆₋₁₀ arylsulfonyl group, an optionallysubstituted 5- to 12-membered monocyclic or polycyclicheterocyclylsulfonyl group, an optionally substituted aminosulfonylgroup, or an optionally substituted 3- to 8-membered cyclicaminosulfonyl group; R² is each independently a hydrogen atom, a halogenatom, a cyano group, a substituted amino group, an optionallysubstituted 3- to 8-membered cyclic amino group, an optionallysubstituted C₁₋₆ alkyl group with the proviso that an unsubstitutedmethyl group is excluded, an optionally substituted C₃₋₁₀ cycloalkylgroup, an optionally substituted C₁₋₆ alkenyl group, an optionallysubstituted C₁₋₆ alkynyl group, an optionally substituted C₆₋₁₀ arylgroup, an optionally substituted 5- to 12-membered monocyclic orpolycyclic heterocyclic group, an optionally substituted C₁₋₆alkylcarbonyl group, an optionally substituted C₃₋₁₀ cycloalkylcarbonylgroup, an optionally substituted C₆₋₁₀ arylcarbonyl group, an optionallysubstituted 5- to 12-membered monocyclic or polycyclicheterocyclylcarbonyl group, a carboxyl group, an optionally substitutedC₁₋₆ alkoxycarbonyl group, an optionally substituted C₃₋₁₀cycloalkyloxycarbonyl group, an optionally substituted C₆₋₁₀aryloxycarbonyl group, an optionally substituted 5- to 12-memberedmonocyclic or polycyclic heterocyclyloxycarbonyl group, an optionallysubstituted aminocarbonyl group, an optionally substituted 3- to8-membered cyclic aminocarbonyl group, an optionally substituted C₁₋₆alkylthio group, an optionally substituted C₃₋₁₀ cycloalkylthio group,an optionally substituted C₆₋₁₀ arylthio group, an optionallysubstituted 5- to 12-membered monocyclic or polycyclic heterocyclylthiogroup, a sulfinate group, an optionally substituted C₁₋₆ alkylsulfinylgroup, an optionally substituted C₃₋₁₀ cycloalkylsulfinyl group, anoptionally substituted C₆₋₁₀ arylsulfinyl group, an optionallysubstituted 5- to 12-membered monocyclic or polycyclicheterocyclylsulfinyl group, an optionally substituted aminosulfinylgroup, an optionally substituted 3- to 8-membered cyclic aminosulfinylgroup, a sulfonate group, an optionally substituted C₁₋₆ alkylsulfonylgroup, an optionally substituted C₃₋₁₀ cycloalkylsulfonyl group, anoptionally substituted C₆₋₁₀ arylsulfonyl group, an optionallysubstituted 5- to 12-membered monocyclic or polycyclicheterocyclylsulfonyl group, an optionally substituted aminosulfonylgroup, or an optionally substituted 3- to 8-membered cyclicaminosulfonyl group; R³, R⁴, or R⁵ is each independently a hydrogenatom, a halogen atom, a cyano group, an hydroxyl group, an optionallysubstituted amino group, an optionally substituted C₁₋₆ alkyl group, anoptionally substituted C₃₋₁₀ cycloalkyl group, an optionally substitutedC₁₋₆ alkenyl group, an optionally substituted C₁₋₆ alkynyl group, anoptionally substituted C₁₋₆ alkoxy group, an optionally substitutedC₆₋₁₀ aryl group, an optionally substituted 5- to 12-membered monocyclicor polycyclic heterocyclic group, an optionally substituted C₁₋₆alkylcarbonyl group, an optionally substituted C₃₋₁₀ cycloalkylcarbonylgroup, an optionally substituted C₆₋₁₀ arylcarbonyl group, an optionallysubstituted 5- to 12-membered monocyclic or polycyclicheterocyclylcarbonyl group, a carboxyl group, an optionally substitutedC₁₋₆ alkoxycarbonyl group, an optionally substituted C₃₋₁₀cycloalkyloxycarbonyl group, an optionally substituted C₆₋₁₀aryloxycarbonyl group, an optionally substituted 5- to 12-memberedmonocyclic or polycyclic heterocyclyloxycarbonyl group, an optionallysubstituted aminocarbonyl group, an optionally substituted C₁₋₆alkylthio group, an optionally substituted C₃₋₁₀ cycloalkylthio group,an optionally substituted C₆₋₁₀ arylthio group, an optionallysubstituted 5- to 12-membered monocyclic or polycyclic heterocyclylthiogroup, a sulfinate group, an optionally substituted C₁₋₆ alkylsulfinylgroup, an optionally substituted C₃₋₁₀ cycloalkylsulfinyl group, anoptionally substituted C₆₋₁₀ arylsulfinyl group, an optionallysubstituted 5- to 12-membered monocyclic or polycyclicheterocyclylsulfinyl group, an optionally substituted aminosulfinylgroup, a sulfonate group, an optionally substituted C₁₋₆ alkylsulfonylgroup, an optionally substituted C₃₋₁₀ cycloalkylsulfonyl group, anoptionally substituted C₆₋₁₀ arylsulfonyl group, an optionallysubstituted 5- to 12-membered monocyclic or polycyclicheterocyclylsulfonyl group, or an optionally substituted aminosulfonylgroup, R⁶ is a hydrogen atom, an optionally substituted C₁₋₆ alkylgroup, an optionally substituted C₃₋₁₀ cycloalkyl group, an optionallysubstituted C₆₋₁₀ aryl group, an optionally substituted 5- to12-membered monocyclic or polycyclic heterocyclic group, an optionallysubstituted C₁₋₆ alkylcarbonyl group, an optionally substituted C₃₋₁₀cycloalkylcarbonyl group, an optionally substituted C₆₋₁₀ arylcarbonylgroup, an optionally substituted 5- to 12-membered monocyclic orpolycyclic heterocyclylcarbonyl group, an optionally substituted C₁₋₆alkoxycarbonyl group, an optionally substituted C₃₋₁₀cycloalkyloxycarbonyl group, an optionally substituted C₆₋₁₀aryloxycarbonyl group, an optionally substituted 5- to 12-memberedmonocyclic or polycyclic heterocyclyloxycarbonyl group, an optionallysubstituted C₁₋₆ alkylsulfinyl group, an optionally substituted C₃₋₁₀cycloalkylsulfinyl group, an optionally substituted C₆₋₁₀ arylsulfinylgroup, an optionally substituted 5- to 12-membered monocyclic orpolycyclic heterocyclylsulfinyl group, an optionally substituted C₁₋₆alkylsulfonyl group, an optionally substituted C₃₋₁₀ cycloalkylsulfonylgroup, an optionally substituted C₆₋₁₀ arylsulfonyl group, or anoptionally substituted 5- to 12-membered monocyclic or polycyclicheterocyclylsulfonyl group, with the proviso that in the formula (1), acompound in which R¹ and R² are both hydrogen atoms, a compound in whichwhen A is O, the ring G is a furan ring or an imidazole ring, a compoundin which when A is S, the ring G is a thiophene ring or an imidazolering, a compound in which when A is N—R⁶, the ring G is a pyrrole ring,a pyrazole ring, or an imidazole ring, an2-isopropylfuro[3,2-g]quinoline-4,9-dione compound, and an ethyl4,8-dioxo-2,7-diphenyl-4,8-dihydrothieno[2,3-f]benzofuran-6-carboxylatecompound are excluded.
 2. The compound of claim 1 or a pharmacologicallyacceptable salt thereof, wherein A is S.
 3. The compound of claim 1 or apharmacologically acceptable salt thereof, wherein A is O.
 4. Thecompound of claim 1 or a pharmacologically acceptable salt thereof,wherein A is N—R⁶.
 5. The compound of claim 1 or a pharmacologicallyacceptable salt thereof, wherein the ring G is chosen from the followingformulas (a) to (l):


6. The compound of claim 5 or a pharmacologically acceptable saltthereof, wherein the ring G is chosen from the following formulas (a) to(h):


7. The compound of claim 6 or a pharmacologically acceptable saltthereof, wherein the ring G is chosen from the following formulas (a) to(f):


8. The compound of claim 1 or a pharmacologically acceptable saltthereof, wherein R¹ is chosen from: 1: a hydrogen atom; 2: a cyanogroup; 3: a C₁₋₆ alkyl group optionally substituted with one to threegroups chosen from a fluorine atom, an hydroxyl group, a C₁₋₆ alkoxygroup, a C₃₋₁₀ cycloalkyl group, a C₆₋₁₀ aryl group, and a 3- to8-membered cyclic amino group; 4: a C₁₋₆ alkylcarbonyl group, whereinthe alkyl group is optionally substituted with one to three groupschosen from a halogen atom, an hydroxyl group, an amino group optionallysubstituted with one or two C₁₋₆ alkyl groups, a C₁₋₆ alkoxy group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₀ aryl group, and a 5- to 12-memberedmonocyclic or polycyclic heterocycle group optionally substituted withone to three C₁₋₆ alkyl groups; 5: a C₆₋₁₀ aryl group optionallysubstituted with one to three groups chosen from a halogen atom, anhydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group; 6: a 5- to12-membered monocyclic or polycyclic heterocycle group optionallysubstituted with one to three groups chosen from a halogen atom, anhydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group; 7: acarboxyl group; 8: an aminocarbonyl group, wherein the amino group isoptionally substituted with one or two groups chosen from (a) a C₁₋₆alkyl group optionally substituted with one to three groups chosen froma halogen atom, an hydroxyl group, a C₁₋₄ alkoxy group, a C₆₋₁₀ arylgroup, and a 5- to 12-membered monocyclic or polycyclic heterocyclegroup optionally substituted with one to three C₁₋₆ alkyl groups, (b) aC₃₋₁₀ cycloalkyl group optionally substituted with one to three groupschosen from a halogen atom, an hydroxyl group, a C₁₋₆ alkyl group, and aC₁₋₆ alkoxy group, (c) a C₆₋₁₀ aryl group optionally substituted withone to three groups chosen from a halogen atom, an hydroxyl group, aC₁₋₆ alkyl group, and a C₁₋₆ alkoxy group, and (d) a 5- to 12-memberedmonocyclic or polycyclic heterocycle group optionally substituted withone to three groups chosen from a halogen atom, an hydroxyl group, aC₁₋₆ alkyl group, and a C₁₋₆ alkoxy group; and 9: a 3- to 8-memberedcyclic aminocarbonyl group, wherein the cyclic amino group is optionallysubstituted with one to three C₁₋₆ alkyl groups.
 9. The compound ofclaim 8 or a pharmacologically acceptable salt thereof, wherein R¹ is ahydrogen atom or a C₁₋₆ alkylcarbonyl group, wherein the alkyl group isoptionally substituted with a 3- to 8-membered cyclic amino group. 10.The compound of claim 1 or a pharmacologically acceptable salt thereof,wherein R² is chosen from 1: a hydrogen atom; 2: a halogen atom; 3: acyano group; 4: an amino group substituted with one or two groups chosenfrom (a) a C₁₋₆ alkyl group optionally substituted with one to threegroups chosen from a halogen atom, an hydroxyl group, a C₁₋₄ alkoxygroup, a C₆₋₁₀ aryl group, and a 5- to 12-membered monocyclic orpolycyclic heterocycle group optionally substituted with one to threeC₁₋₆ alkyl groups, (b) a C₁₋₆ alkylcarbonyl group, wherein the alkyl isoptionally substituted with one to three groups chosen from a halogenatom, an hydroxyl group, a C₁₋₄ alkoxy group, a C₆₋₁₀ aryl group, and a5- to 12-membered monocyclic or polycyclic heterocycle group optionallysubstituted with one to three C₁₋₆ alkyl groups, (c) a C₃₋₁₀ cycloalkylgroup optionally substituted with one to three groups chosen from ahalogen atom, an hydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxygroup, (d) a C₆₋₁₀ aryl group optionally substituted with one to threegroups chosen from a halogen atom, an hydroxyl group, a C₁₋₆ alkylgroup, and a C₁₋₆ alkoxy group, and (e) a 5- to 12-membered monocyclicor polycyclic heterocycle group optionally substituted with one to threegroups chosen from a halogen atom, an hydroxy group, a C₁₋₆ alkyl group,and a C₁₋₆ alkoxy group; 5: a 3- to 8-membered cyclic amino groupoptionally substituted with one to three C₁₋₆ alkyl groups; 6: a C₁₋₆alkyl group optionally substituted with one to three groups chosen from(a) a halogen atom, (b) an hydroxyl group, (c) an amino group optionallysubstituted with one or two groups chosen from (i) a C₁₋₆ alkyl groupoptionally substituted with one to three groups chosen from a halogenatom, an hydroxyl group, a C₁₋₄ alkoxy group, an aminocarbonyl group,wherein the amino group is optionally substituted with one to three C₁₋₆alkyl groups, a C₆₋₁₀ aryl group, and a 5- to 12-membered monocyclic orpolycyclic heterocycle group optionally substituted with one to threeC₁₋₆ alkyl groups, (ii) a C₃₋₈ cycloalkyl group optionally substitutedwith one to three groups chosen from a halogen atom, an hydroxyl group,a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group, (iii) a C₁₋₆ alkylcarbonylgroup, wherein the alkyl group is optionally substituted with one tothree groups chosen from a halogen atom, an hydroxy group, a C₁₋₄ alkoxygroup, a C₆₋₁₀ aryl group, or a 5- to 12-membered monocyclic orpolycyclic heterocycle group optionally substituted with one to threeC₁₋₆ alkyl groups, (iv) a C₁₋₆ alkoxycarbonyl group, wherein the alkylgroup is optionally substituted with one to three groups chosen from ahalogen atom, an hydroxyl group, a C₁₋₄ alkoxy group, a C₆₋₁₀ arylgroup, and a 5- to 12-membered monocyclic or polycyclic heterocyclegroup optionally substituted with one to three C₁₋₆ alkyl groups, (v) aC₁₋₆ alkylsulfinyl group, wherein the alkyl group is optionallysubstituted with one to three groups chosen from a halogen atom, anhydroxyl group, a C₁₋₄ alkoxy group, a C₆₋₁₀ aryl group, and a 5- to12-membered monocyclic or polycyclic heterocycle group optionallysubstituted with one to three C₁₋₆ alkyl groups, (vi) a C₁₋₆alkylsulfonyl group, wherein the alkyl group is optionally substitutedwith one to three groups chosen from a halogen atom, an hydroxyl group,a C₁₋₄ alkoxy group, a C₆₋₁₀ aryl group, and a 5- to 12-memberedmonocyclic or polycyclic heterocycle group optionally substituted withone to three C₁₋₆ alkyl groups, (vii) an aminocarbonyl group, whereinthe amino group is optionally substituted with one or two C₁₋₆ alkylgroups optionally substituted with one to three groups chosen from ahalogen atom, an hydroxyl group, a C₁₋₄ alkoxy group, a C₆₋₁₀ arylgroup, and a 5- to 12-membered monocyclic or polycyclic heterocyclegroup optionally substituted with one to three C₁₋₆ alkyl groups, (viii)a 3- to 8-membered cyclic amino group optionally substituted with one tothree C₁₋₆ alkyl groups, and (ix) a C₃₋₁₀ cycloalkylcarbonyl group, (d)a 3- to 8-membered cyclic amino group optionally substituted with one tothree C₁₋₆ alkylcarbonyl group, (e) a C₁₋₆ alkoxy group optionallysubstituted with one to three C₆₋₁₀ aryl groups, (f) a C₃₋₁₀ cycloalkylgroup, (g) a C₆₋₁₀ aryl group, and (h) a 5- to 12-membered monocyclic orpolycyclic heterocycle group; 7: a C₃₋₁₀ cycloalkyl group optionallysubstituted with one to three groups chosen from a halogen atom, anhydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group; 8: a C₁₋₆alkenyl group optionally substituted with one to three groups chosenfrom C₁₋₆ alkyl and C₁₋₆ alkoxycarbonyl groups; 9: a C₁₋₆ alkynyl groupoptionally substituted with one to three groups chosen from C₁₋₆ alkyland C₁₋₆ alkoxycarbonyl groups; 10: a C₆₋₁₀ aryl group optionallysubstituted with one to three groups chosen from a halogen atom, anhydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group; 11: a 5- to12-membered monocyclic or polycyclic heterocyclic group, wherein theheterocycle group is optionally substituted with one to three groupschosen from a halogen atom, an hydroxyl group, a C₁₋₆ alkyl group, and aC₁₋₆ alkoxy group; 12: a C₃₋₁₀ cycloalkyloxy group, wherein thecycloalkyl group is optionally substituted with one to three groupschosen from a halogen atom, an hydroxyl group, a C₁₋₆ alkyl group, and aC₁₋₆ alkoxy group; 13: a C₆₋₁₀ aryloxy group, wherein the aryl group isoptionally substituted with one to three groups chosen from a halogenatom, an hydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group;14: a 5- to 12-membered monocyclic or polycyclic heterocyclyloxy group,wherein the heterocycle group is optionally substituted with one tothree groups chosen from a halogen atom, an hydroxyl group, a C₁₋₆ alkylgroup, and a C₁₋₆ alkoxy group; 15: a carboxyl group; 16: a C₁₋₆alkylcarbonyl group, wherein the alkyl group is optionally substitutedwith one to three groups chosen from a halogen atom, an hydroxyl group,an amino group optionally substituted with one or two C₁₋₆ alkyl groups,a C₁₋₆ alkoxy group, a C₃₋₁₀ cycloalkyl group, a C₆₋₁₀ aryl group, and a5- to 12-membered monocyclic or polycyclic heterocycle group; 17: aC₃₋₁₀ cycloalkylcarbonyl group, wherein the cycloalkyl group isoptionally substituted with one to three groups chosen from a halogenatom, an hydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group;18: a C₆₋₁₀ arylcarbonyl group, wherein the aryl group is optionallysubstituted with one to three groups chosen from a halogen atom, anhydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group; 19: a 5- to12-membered monocyclic or polycyclic heterocyclylcarbonyl group, whereinthe heterocycle group is optionally substituted with one to three groupschosen from a halogen atom, an hydroxyl group, a C₁₋₆ alkyl group, and aC₁₋₆ alkoxy group; 20: a C₃₋₁₀ cycloalkyloxycarbonyl group, wherein thecycloalkyl group is optionally substituted with one to three groupschosen from a halogen atom, an hydroxyl group, a C₁₋₆ alkyl group, and aC₁₋₆ alkoxy group; 21: a C₆₋₁₀ aryloxycarbonyl group, wherein the arylgroup is optionally substituted with one to three groups chosen from ahalogen atom, an hydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxygroup; 22: a 5- to 12-membered monocyclic or polycyclicheterocyclyloxycarbonyl group, wherein the heterocycle is optionallysubstituted with one to three groups chosen from a halogen atom, anhydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group; 23: anaminocarbonyl group, wherein the amino group is optionally substitutedwith one or two groups chosen from (a) a C₁₋₆ alkyl group optionallysubstituted with one to three groups chosen from a halogen atom, anhydroxyl group, a C₁₋₄ alkoxy group, a C₆₋₁₀ aryl group, and a 5- to12-membered monocyclic or polycyclic heterocycle group optionallysubstituted with one to three C₁₋₆ alkyl groups, (b) a C₃₋₁₀ cycloalkylgroup optionally substituted with one to three groups chosen from ahalogen atom, an hydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxygroup), (c) a C₆₋₁₀ aryl group, wherein the aryl is optionallysubstituted with one to three groups chosen from a halogen atom, anhydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group, and (d) a5- to 12-membered monocyclic or polycyclic heterocycle group optionallysubstituted with one to three groups chosen from a halogen atom, anhydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group; 24: a 3- to8-membered cyclic aminocarbonyl group, wherein the cyclic amino isoptionally substituted with one to three C₁₋₆ alkyl groups; 25: a C₁₋₆alkylthio group, wherein the alkyl group is optionally substituted withone to three groups chosen from a halogen atom, an hydroxyl group, anamino group optionally substituted with one or two C₁₋₆ alkyl groups, aC₁₋₆ alkoxy group, a C₃₋₁₀ cycloalkyl group, a C₆₋₁₀ aryl group, and a5- to 12-membered monocyclic or polycyclic heterocycle group; 26: aC₃₋₁₀ cycloalkylthio group, wherein the cycloalkyl group is optionallysubstituted with one to three groups chosen from a halogen atom, anhydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group; 27: a C₆₋₁₀arylthio group, wherein the aryl group is optionally substituted withone to three groups chosen from a halogen atom, an hydroxyl group, aC₁₋₆ alkyl group, and a C₁₋₆ alkoxy group; 28: a 5- to 12-memberedmonocyclic or polycyclic heterocyclylthio group, wherein the heterocyclegroup is optionally substituted with one to three groups chosen from ahalogen atom, an hydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxygroup; 29: a sulfinate group; 30: a C₁₋₆ alkylsulfinyl group, whereinthe alkyl group is optionally substituted with one to three groupschosen from a halogen atom, an hydroxyl group, an amino group optionallysubstituted with one or two C₁₋₆ alkyl groups, a C₁₋₆ alkoxy group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₀ aryl group, and a 5- to 12-memberedmonocyclic or polycyclic heterocycle group; 31: a C₃₋₁₀cycloalkylsulfinyl group, wherein the cycloalkyl group is optionallysubstituted with one to three groups chosen from a halogen atom, anhydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group; 32: a C₆₋₁₀arylsulfinyl group, wherein the aryl group is optionally substitutedwith one to three groups chosen from a halogen atom, an hydroxyl group,a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group; 33: a 5- to 12-memberedmonocyclic or polycyclic heterocyclylsulfinyl group, wherein theheterocycle group is optionally substituted with one to three groupschosen from a halogen atom, an hydroxyl group, a C₁₋₆ alkyl group, and aC₁₋₆ alkoxy group; 34: an aminosulfinyl group, wherein the amino groupis optionally substituted with one or two groups chosen from (a) a C₁₋₆alkyl group optionally substituted with one to three groups chosen froma halogen atom, an hydroxyl group, a C₁₋₄ alkoxy group, a C₆₋₁₀ arylgroup, and a 5- to 12-membered monocyclic or polycyclic heterocyclegroup optionally substituted with one to three C₁₋₆ alkyl group, (b) aC₃₋₁₀ cycloalkyl group optionally substituted with one to three groupschosen from a halogen atom, an hydroxyl group, a C₁₋₆ alkyl group, and aC₁₋₆ alkoxy group, (c) a C₆₋₁₀ aryl group optionally substituted withone to three groups chosen from a halogen atom, an hydroxyl group, aC₁₋₆ alkyl group, and a C₁₋₆ alkoxy group, and (d) a 5- to 12-memberedmonocyclic or polycyclic heterocycle group wherein the heterocycle isoptionally substituted with one to three groups chosen from a halogenatom, an hydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group;35: a 3- to 8-membered cyclic aminosulfinyl group, wherein the cyclicamino group is optionally substituted with one to three C₁₋₆ alkylgroups; 36: a sulfonate group; 37: a C₁₋₆ alkylsulfonyl group, whereinthe alkyl is optionally substituted with one to three groups chosen froma halogen atom, an hydroxyl group, an amino group optionally substitutedwith one or two C₁₋₆ alkyl groups, a C₁₋₆ alkoxy group, a C₃₋₁₀cycloalkyl group, a C₆₋₁₀ aryl group, and a 5- to 12-membered monocyclicor polycyclic heterocycle group; 38: a C₃₋₁₀ cycloalkylsulfonyl group,wherein the cycloalkyl group is optionally substituted with one to threegroups chosen from a halogen atom, an hydroxyl group, a C₁₋₆ alkylgroup, and a C₁₋₆ alkoxy group; 39: a C₆₋₁₀ arylsulfonyl group, whereinthe aryl group is optionally substituted with one to three groups chosenfrom a halogen atom, an hydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆alkoxy group; 40: a 5- to 12-membered monocyclic or polycyclicheterocyclylsulfonyl group, wherein the heterocycle group is optionallysubstituted with one to three groups chosen from a halogen atom, anhydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group; 41: anaminosulfonyl group wherein the amino group is optionally substitutedwith one or two groups chosen from (a) a C₁₋₆ alkyl group optionallysubstituted with one to three groups chosen from a halogen atom, anhydroxyl group, a C₁₋₄ alkoxy group, a C₆₋₁₀ aryl group, and a 5- to12-membered monocyclic or polycyclic heterocycle group optionallysubstituted with one to three C₁₋₆ alkyl, (b) a C₃₋₁₀ cycloalkyl groupoptionally substituted with one to three groups chosen from a halogenatom, an hydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group,(c) a C₆₋₁₀ aryl group optionally substituted with one to three groupschosen from a halogen atom, an hydroxyl group, a C₁₋₆ alkyl group, and aC₁₋₆ alkoxy group, and (d) a 5- to 12-membered monocyclic or polycyclicheterocycle group, wherein the heterocycle group is optionallysubstituted with one to three groups chosen from a halogen atom, anhydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group; and 42: a3- to 8-membered cyclic aminosulfinyl group, wherein the cyclic aminogroup is optionally substituted with one to three C₁₋₆ alkyl groups. 11.The compound of claim 10 or a pharmacologically acceptable salt thereof,wherein R² is a group chosen from: 1: a hydrogen atom; 2: a halogenatom; 3: a cyano group; 4: an amino group optionally substituted withone to three C₁₋₆ alkyl groups; 5: a 3- to 8-membered cyclic aminogroup, wherein the cyclic amino group is optionally substituted with oneto three C₁₋₆ alkyl groups; 6: a C₁₋₆ alkyl group optionally substitutedwith one to three groups chosen from (a) a halogen atom, (b) an hydroxylgroup, (c) an amino group optionally substituted with one or two groupschosen from (i) a C₁₋₆ alkyl group optionally substituted with one tothree groups chosen from a halogen atom, an hydroxyl group, and a C₁₋₄alkoxy group, (ii) a C₃₋₈ cycloalkyl group, (iii) a C₁₋₆ alkylcarbonylgroup, (iv) a C₁₋₆ alkoxycarbonyl group, and (v) a C₁₋₆ alkylsulfonylgroup, (d) a 3- to 8-membered cyclic amino group, (e) a C₁₋₆ alkoxygroup, (f) a C₃₋₁₀ cycloalkyl group, (g) a phenyl group, and (h) a 5- to6-membered monocyclic or polycyclic heterocycle group; 7: a C₁₋₆ alkenylgroup optionally substituted with one to three groups chosen from a C₁₋₆alkyl and C₁₋₆ alkoxycarbonyl groups; 8: a C₁₋₆ alkynyl group optionallysubstituted with one to three groups chosen from C₁₋₆ alkyl and C₁₋₆alkoxycarbonyl groups; 9: a 5- to 12-membered monocyclic or polycyclicheterocyclic group; 10: a C₁₋₆ alkylcarbonyl group, wherein the alkylgroup is optionally substituted with one to three groups chosen from ahalogen atom, an hydroxyl group, an amino group optionally substitutedwith one or two C₁₋₆ alkyl groups, a C₁₋₄ alkoxy group, a C₃₋₈cycloalkyl group, a phenyl group, and a 5- to 6-membered monocyclicheterocycle group optionally substituted with one to three C₁₋₆ alkylgroups; 11: an aminocarbonyl group, wherein the amino group isoptionally substituted with one to three groups chosen from (a) a C₁₋₆alkyl group optionally substituted with one to three groups chosen froma halogen atom, an hydroxyl group, a C₁₋₄ alkoxy group, a phenyl group,and a 5- to 6-membered monocyclic heterocycle group optionallysubstituted with one to three C₁₋₄ alkyl groups, (b) a C₃₋₈ cycloalkylgroup optionally substituted with one to three groups chosen from ahalogen atom, an hydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxygroup, (c) a phenyl group, wherein the aryl group is optionallysubstituted with one to three groups chosen from a halogen atom, anhydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group, and (d) a5- to 6-membered monocyclic heterocycle group optionally substitutedwith one to three groups chosen from a halogen atom, an hydroxyl group,a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group; and 12: a 3- to 8-memberedcyclic aminocarbonyl group, wherein the cyclic amino group is optionallysubstituted with one to three C₁₋₆ alkyl groups.
 12. The compound ofclaim 11 or a pharmacologically acceptable salt thereof, wherein R² is agroup chosen from: 1: a C₁₋₆ alkyl group optionally substituted with oneto three groups chosen from a halogen atom, an hydroxyl group, an aminogroup optionally substituted with one or two C₁₋₆ alkyl groups, a C₁₋₄alkoxy group, a C₃₋₈ cycloalkyl group, a phenyl group, and a 5- to6-membered monocyclic heterocycle group; 2: a C₁₋₆ alkylcarbonyl group,wherein the alkyl is optionally substituted with one to three groupschosen from a halogen atom, an hydroxyl group, an amino group optionallysubstituted with one or two C₁₋₆ alkyl groups, a C₁₋₄ alkoxy group, aC₃₋₈ cycloalkyl group, a phenyl group, and a 5- to 6-membered monocyclicheterocycle group optionally substituted with one to three C₁₋₆ alkylgroup; 3: an aminocarbonyl group, wherein the amino group is optionallysubstituted with one or two groups chosen from (a) a C₁₋₆ alkyl groupoptionally substituted with one to three groups chosen from a halogenatom, an hydroxyl group, a C₁₋₄ alkoxy group, a phenyl group, and a 5-to 6-membered monocyclic heterocycle group optionally substituted withone to three C₁₋₄ alkyl group, (b) a C₃₋₈ cycloalkyl group optionallysubstituted with one to three groups chosen from a halogen atom, anhydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group, (c) aphenyl group, wherein the aryl is optionally substituted with one tothree groups chosen from a halogen atom, an hydroxyl group, a C₁₋₆ alkylgroup, and a C₁₋₆ alkoxy group, and (d) a 5- to 6-membered monocyclicheterocycle group optionally substituted with one to three groups chosenfrom a halogen atom, an hydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆alkoxy group; and 4: a 3- to 8-membered cyclic aminocarbonyl group,wherein the cyclic amino group is optionally substituted with one tothree C₁₋₆ alkyl groups.
 13. The compound of claim 1 or apharmacologically acceptable salt thereof, wherein R³, R⁴, or R⁵ is eachindependently a group chosen from: 1: a hydrogen atom; 2: a halogenatom; 3: a cyano group; 4: an hydroxyl group; 5: an amino groupoptionally substituted with one or two groups chosen from (a) C₁₋₆ alkyloptionally substituted with one to three groups chosen from a halogenatom, an hydroxyl group, a C₁₋₄ alkoxy group, a C₆₋₁₀ aryl group, and a5- to 12-membered monocyclic or polycyclic heterocycle group optionallysubstituted with one to three C₁₋₆ alkyl groups, (b) C₁₋₆ alkylcarbonyl,wherein the alkyl group is optionally substituted with one to threegroups chosen from a halogen atom, an hydroxyl group, a C₁₋₄ alkoxygroup, a C₆₋₁₀ aryl group, and a 5- to 12-membered monocyclic orpolycyclic heterocycle group optionally substituted with one to threeC₁₋₆ alkyl groups, (c) C₃₋₁₀ cycloalkyl group, wherein the cycloalkyl isoptionally substituted with one to three groups chosen from a halogenatom, an hydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group,(d) C₆₋₁₀ aryl group, wherein the aryl is optionally substituted withone to three groups chosen from a halogen atom, an hydroxyl group, aC₁₋₆ alkyl group, and a C₁₋₆ alkoxy group, and (e) a 5- to 12-memberedmonocyclic or polycyclic heterocycle group, wherein the heterocycle isoptionally substituted with one to three groups chosen from a halogenatom, an hydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group; 6:a 3- to 8-membered cyclic amino group optionally substituted with one tothree C₁₋₆ alkyl group; 7: a C₁₋₆ alkyl group optionally substitutedwith one to three groups chosen from a halogen atom, an hydroxyl group,an amino group optionally substituted with one or two C₁₋₆ alkyl groups,a C₁₋₆ alkoxy group, a C₃₋₁₀ cycloalkyl group, a C₆₋₁₀ aryl group, and a5- to 12-membered monocyclic or polycyclic heterocycle group; 8: a C₃₋₁₀cycloalkyl group optionally substituted with one to three groups chosenfrom a halogen atom, an hydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆alkoxy group); 9: a C₆₋₁₀ aryl group optionally substituted with one tothree groups chosen from a halogen atom, an hydroxyl group, a C₁₋₆ alkylgroup, and a C₁₋₆ alkoxy group; 10: a 5- to 12-membered monocyclic orpolycyclic heterocyclic group, wherein the heterocycle is optionallysubstituted with one to three groups chosen from a halogen atom, anhydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group; 11: a C₁₋₆alkoxy group, wherein the alkyl group is optionally substituted with oneto three groups chosen from a halogen atom, an hydroxyl group, an aminogroup optionally substituted with one or two C₁₋₆ alkyl groups, a C₁₋₆alkoxy group, a C₃₋₁₀ cycloalkyl group, a C₆₋₁₀ aryl group, and a 5- to12-membered monocyclic or polycyclic heterocycle; 12: a C₃₋₁₀cycloalkyloxy group, wherein the cycloalkyl group is optionallysubstituted with one to three groups chosen from a halogen atom, anhydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group; 13: a C₆₋₁₀aryloxy group, wherein the aryl group is optionally substituted with oneto three groups chosen from a halogen atom, an hydroxyl group, a C₁₋₆alkyl group, and a C₁₋₆ alkoxy group; 14: a 5- to 12-membered monocyclicor polycyclic heterocyclyloxy group, wherein the heterocycle isoptionally substituted with one to three groups chosen from a halogenatom, an hydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group;15: a carboxyl group; 16: a C₁₋₆ alkylcarbonyl group, wherein the alkylgroup is optionally substituted with one to three groups chosen from ahalogen atom, an hydroxyl group, an amino group optionally substitutedwith one or two C₁₋₆ alkyl groups, a C₁₋₆ alkoxy group, a C₃₋₁₀cycloalkyl group, a C₆₋₁₀ aryl group, and a 5- to 12-membered monocyclicor polycyclic heterocycle group; 17: a C₃₋₁₀ cycloalkylcarbonyl group,wherein the cycloalkyl group is optionally substituted with one to threegroups chosen from a halogen atom, an hydroxyl group, a C₁₋₆ alkylgroup, and a C₁₋₆ alkoxy group; 18: a C₆₋₁₀ arylcarbonyl group, whereinthe aryl group is optionally substituted with one to three groups chosenfrom a halogen atom, an hydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆alkoxy group; 19: a 5- to 12-membered monocyclic or polycyclicheterocyclylcarbonyl group, wherein the heterocycle group is optionallysubstituted with one to three groups chosen from a halogen atom, anhydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group; 20: a C₁₋₆alkoxycarbonyl group, wherein the alkyl group is optionally substitutedwith one to three groups chosen from a halogen atom, an hydroxyl group,an amino group optionally substituted with one or two C₁₋₆ alkyl groups,a C₁₋₆ alkoxy group, a C₃₋₁₀ cycloalkyl group; a C₆₋₁₀ aryl group, and a5- to 12-membered monocyclic or polycyclic heterocycle group; 21: aC₃₋₁₀ cycloalkyloxycarbonyl group, wherein the cycloalkyl group isoptionally substituted with one to three groups chosen from a halogenatom, an hydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group;22: a C₆₋₁₀ aryloxycarbonyl group, wherein the aryl is optionallysubstituted with one to three groups chosen from a halogen atom, anhydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group; 23: a 5- to12-membered monocyclic or polycyclic heterocyclyloxycarbonyl group,wherein the heterocycle group is optionally substituted with one tothree groups chosen from a halogen atom, an hydroxyl group, a C₁₋₆alkyl, and a C₁₋₆ alkoxy; 24: an aminocarbonyl group, wherein the aminogroup is optionally substituted with one or two groups chosen from (a) aC₁₋₆ alkyl group optionally substituted with one to three groups chosenfrom a halogen atom, an hydroxyl group, a C₁₋₄ alkoxy group, a C₆₋₁₀aryl group, and a 5- to 12-membered monocyclic or polycyclic heterocyclegroup optionally substituted with one to three C₁₋₆ alkyl groups, (b) aC₃₋₁₀ cycloalkyl group optionally substituted with one to three groupschosen from a halogen atom, an hydroxyl group, a C₁₋₆ alkyl group, and aC₁₋₆ alkoxy group, (c) a C₆₋₁₀ aryl group optionally substituted withone to three groups chosen from a halogen atom, an hydroxyl group, aC₁₋₆ alkyl group, and a C₁₋₆ alkoxy group, and (d) a 5- to 12-memberedmonocyclic or polycyclic heterocycle, wherein the heterocycle group isoptionally substituted with one to three groups chosen from a halogenatom, an hydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group;25: a 3- to 8-membered cyclic aminocarbonyl group, wherein the cyclicamino group is optionally substituted with one to three C₁₋₆ alkylgroups; 26: a C₁₋₆ alkylthio group, wherein the alkyl group isoptionally substituted with one to three groups chosen from a halogenatom, an hydroxyl group, an amino group optionally substituted with oneor two C₁₋₆ alkyl groups, a C₁₋₆ alkoxy group, a C₃₋₁₀ cycloalkyl group,a C₆₋₁₀ aryl group, and a 5- to 12-membered monocyclic or polycyclicheterocycle group; 27: a C₃₋₁₀ cycloalkylthio group, wherein thecycloalkyl group is optionally substituted with one to three groupschosen from a halogen atom, an hydroxyl group, a C₁₋₆ alkyl group, and aC₁₋₆ alkoxy group; 28: a C₆₋₁₀ arylthio group, wherein the aryl group isoptionally substituted with one to three groups chosen from a halogenatom, an hydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group;29: a 5- to 12-membered monocyclic or polycyclic heterocyclylthio group,wherein the heterocycle group is optionally substituted with one tothree groups chosen from a halogen atom, an hydroxyl group, a C₁₋₆ alkylgroup, and a C₁₋₆ alkoxy group; 30: a sulfinate group; 31: a C₁₋₆alkylsulfinyl group, wherein the alkyl group is optionally substitutedwith one to three groups chosen from a halogen atom, an hydroxyl group,an amino group optionally substituted with one or two C₁₋₆ alkyl group,a C₁₋₆ alkoxy group, a C₃₋₁₀ cycloalkyl group, a C₆₋₁₀ aryl group, and a5- to 12-membered monocyclic or polycyclic heterocycle group; 32: aC₃₋₁₀ cycloalkylsulfinyl group, wherein the cycloalkyl group isoptionally substituted with one to three groups chosen from a halogenatom, an hydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group;33: a C₆₋₁₀ arylsulfinyl group, wherein the aryl group is optionallysubstituted with one to three groups chosen from a halogen atom, anhydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group; 34: a 5- to12-membered monocyclic or polycyclic heterocyclylsulfinyl group, whereinthe heterocycle group is optionally substituted with one to three groupschosen from a halogen atom, an hydroxyl group, a C₁₋₆ alkyl group, and aC₁₋₆ alkoxy group; 35: an aminosulfinyl group, wherein the amino groupis optionally substituted with one or two groups chosen from (a) a C₁₋₆alkyl group optionally substituted with one to three groups chosen froma halogen atom, an hydroxyl group, a C₁₋₄ alkoxy group, a C₆₋₁₀ arylgroup, and a 5- to 12-membered monocyclic or polycyclic heterocyclesubstituted with one to three C₁₋₆ alkyl groups, (b) a C₃₋₁₀ cycloalkylgroup optionally substituted with one to three groups chosen from ahalogen atom, an hydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxygroup, (c) a C₆₋₁₀ aryl group optionally substituted with one to threegroups chosen from a halogen atom, an hydroxyl group, a C₁₋₆ alkylgroup, and a C₁₋₆ alkoxy group, and (d) a 5- to 12-membered monocyclicor polycyclic heterocycle group, wherein the heterocycle group isoptionally substituted with one to three groups chosen from a halogenatom, an hydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group;36: a 3- to 8-membered cyclic aminosulfinyl group, wherein the cyclicamino group is optionally substituted with one to three C₁₋₆ alkylgroups; 37: a sulfonate group; 38: a C₁₋₆ alkylsulfonyl group, whereinthe alkyl group is optionally substituted with one to three groupschosen from a halogen atom, an hydroxyl group, an amino group optionallysubstituted with one or two C₁₋₆ alkyl group, a C₁₋₆ alkoxy group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₀ aryl group, and a 5- to 12-memberedmonocyclic or polycyclic heterocycle group; 39: a C₃₋₁₀cycloalkylsulfonyl group, wherein the cycloalkyl group is optionallysubstituted with one to three groups chosen from a halogen atom, anhydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group; 40: a C₆₋₁₀arylsulfonyl group, wherein the aryl group is optionally substitutedwith one to three groups chosen from a halogen atom, an hydroxyl group,a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group; 41: a 5- to 12-memberedmonocyclic or polycyclic heterocyclylsulfonyl group, wherein theheterocycle group is optionally substituted with one to three groupschosen from a halogen atom, an hydroxyl group, a C₁₋₆ alkyl group, and aC₁₋₆ alkoxy group; 42: an aminosulfonyl group, wherein the amino groupis optionally substituted with one or two groups chosen from (a) a C₁₋₆alkyl group optionally substituted with one to three groups chosen froma halogen atom, an hydroxyl group, a C₁₋₄ alkoxy group, a C₆₋₁₀ arylgroup, and a 5- to 12-membered monocyclic or polycyclic heterocyclegroup optionally substituted with one to three C₁₋₆ alkyl groups, (b) aC₃₋₁₀ cycloalkyl group optionally substituted with one to three groupschosen from a halogen atom, an hydroxyl group, a C₁₋₆ alkyl group, and aC₁₋₆ alkoxy group, (c) a C₆₋₁₀ aryl group optionally substituted withone to three groups chosen from a halogen atom, an hydroxyl group, aC₁₋₆ alkyl group, and a C₁₋₆ alkoxy group, and (d) a 5- to 12-memberedmonocyclic or polycyclic heterocycle group optionally substituted withone to three groups chosen from a halogen atom, an hydroxyl group, aC₁₋₆ alkyl group, and a C₁₋₆ alkoxy group; and 43: a 3- to 8-memberedcyclic aminosulfonyl group, wherein the cyclic amino group is optionallysubstituted with one to three C₁₋₆ alkyl groups.
 14. The compound ofclaim 13 or a pharmacologically acceptable salt thereof, wherein R³, R⁴,or R⁵ is each independently a group chosen from: 1: a hydrogen atom; 2:a halogen atom; 3: a cyano group; 4: an hydroxyl group; 5: an aminogroup optionally substituted with one or two groups chosen from (a) aC₁₋₆ alkyl optionally substituted with one to three groups chosen from ahalogen atom, an hydroxyl group, a C₁₋₄ alkoxy group, a C₆₋₁₀ arylgroup, and a 5- to 12-membered monocyclic or polycyclic heterocyclegroup optionally substituted with one to three C₁₋₆ alkyl groups, (b) aC₁₋₆ alkylcarbonyl group, wherein the alkyl group is optionallysubstituted with one to three groups chosen from a halogen atom, anhydroxyl group, a C₁₋₄ alkoxy group, a C₆₋₁₀ aryl group, and a 5- to12-membered monocyclic or polycyclic heterocycle group optionallysubstituted with one to three C₁₋₆ alkyl groups, (c) a C₃₋₁₀ cycloalkylgroup optionally substituted with one to three groups chosen from ahalogen atom, an hydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxygroup, (d) a C₆₋₁₀ aryl (wherein the aryl is optionally substituted withone to three groups chosen from a halogen atom, an hydroxyl group, aC₁₋₆ alkyl group, and a C₁₋₆ alkoxy group, and (e) a 5- to 12-memberedmonocyclic or polycyclic heterocycle group, wherein the heterocycle isoptionally substituted with one to three groups chosen from a halogenatom, an hydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group; 6:a 3- to 8-membered cyclic amino group optionally substituted with one tothree C₁₋₆ alkyl groups; 7: a C₁₋₆ alkyl group optionally substitutedwith one to three groups chosen from a halogen atom, an hydroxyl group,an amino group optionally substituted with one or two C₁₋₆ alkyl groups,a C₁₋₆ alkoxy group, a C₃₋₁₀ cycloalkyl group, a C₆₋₁₀ aryl group, and a5- to 12-membered monocyclic or polycyclic heterocycle group; 8: a C₁₋₆alkoxy group optionally substituted with one to three groups chosen froma halogen atom, an hydroxyl group, an amino group optionally substitutedwith one or two C₁₋₆ alkyl groups, a C₁₋₆ alkoxy group, a C₃₋₁₀cycloalkyl group, a C₆₋₁₀ aryl group, and a 5- to 12-membered monocyclicor polycyclic heterocycle group; 9: a C₁₋₆ alkylcarbonyl group, whereinthe alkyl group is optionally substituted with one to three groupschosen from a halogen atom, an hydroxyl group, an amino group optionallysubstituted with one or two C₁₋₆ alkyl groups, a C₁₋₆ alkoxy group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₀ aryl group, and a 5- to 12-memberedmonocyclic or polycyclic heterocycle group; 10: an aminocarbonyl group,wherein the amino group is optionally substituted with one or two groupschosen from (a) a C₁₋₆ alkyl group optionally substituted with one tothree groups chosen from a halogen atom, an hydroxyl group, a C₁₋₄alkoxy group, a C₆₋₁₀ aryl group, and a 5- to 12-membered monocyclic orpolycyclic heterocycle group optionally substituted with one to threeC₁₋₆ alkyl groups, (b) a C₃₋₁₀ cycloalkyl group optionally substitutedwith one to three groups chosen from a halogen atom, an hydroxyl group,a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group, (c) a C₆₋₁₀ aryl group,wherein the aryl is optionally substituted with one to three groupschosen from a halogen atom, an hydroxyl group, a C₁₋₆ alkyl group, and aC₁₋₆ alkoxy group, and (d) a 5- to 12-membered monocyclic or polycyclicheterocycle group, wherein the heterocycle is optionally substitutedwith one to three groups chosen from a halogen atom, an hydroxyl group,a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group; 11: a 3- to 8-memberedcyclic aminocarbonyl group, wherein the cyclic amino group is optionallysubstituted with one to three C₁₋₆ alkyl groups; 12: a C₁₋₆alkylsulfonyl group, wherein the alkyl group is optionally substitutedwith one to three groups chosen from a halogen atom, an hydroxyl group,an amino group optionally substituted with one or two C₁₋₆ alkyl groups,a C₁₋₆ alkoxy group, a C₃₋₁₀ cycloalkyl group, a C₆₋₁₀ aryl group, and a5- to 12-membered monocyclic or polycyclic heterocycle group; 13: anaminosulfonyl group, wherein the amino group is optionally substitutedwith one or two groups chosen from (a) a C₁₋₆ alkyl group optionallysubstituted with one to three groups chosen from a halogen atom, anhydroxyl group, a C₁₋₄ alkoxy group, a C₆₋₁₀ aryl group, and a 5- to12-membered monocyclic or polycyclic heterocycle optionally substitutedwith one to three C₁₋₆ alkyl groups, (b) a C₃₋₁₀ cycloalkyl groupoptionally substituted with one to three groups chosen from a halogenatom, an hydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group,(c) a C₆₋₁₀ aryl group optionally substituted with one to three groupschosen from a halogen atom, an hydroxyl group, a C₁₋₆ alkyl group, and aC₁₋₆ alkoxy group, and (d) a 5- to 12-membered monocyclic or polycyclicheterocycle group, wherein the heterocycle group is optionallysubstituted with one to three groups chosen from a halogen atom, anhydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group; and 14: a3- to 8-membered cyclic aminosulfonyl group, wherein the cyclic aminogroup is optionally substituted with one to three C₁₋₆ alkyl groups. 15.The compound of claim 14 or a pharmacologically acceptable salt thereof,wherein R³, R⁴, and/or R⁵ is a hydrogen atoms.
 16. The compound of claim1 or a pharmacologically acceptable salt thereof, wherein R⁶ is a groupchosen from: 1: a hydrogen atom; 2: a C₁₋₆ alkyl group optionallysubstituted with one to three groups chosen from a halogen atom, C₁₋₆alkoxy group, C₆₋₁₀ aryl group, and a 5- to 6-membered monocyclicheterocycle optionally substituted with one to three C₁₋₄ alkyl groups;3: a C₃₋₁₀ cycloalkyl group optionally substituted with one to threegroups chosen from a halogen atom, an hydroxyl group, a C₁₋₆ alkylgroup, and a C₁₋₆ alkoxy group; 4: a C₁₋₆ alkylcarbonyl group, whereinthe alkyl group is optionally substituted with one to three groupschosen from a halogen atom, a C₁₋₆ alkoxy group, a C₆₋₁₀ aryl group, anda 5- to 6-membered monocyclic heterocycle group optionally substitutedwith one to three C₁₋₄ alkyl groups; 5: a C₃₋₁₀ cycloalkylcarbonylgroup; 6: a C₆₋₁₀ arylcarbonyl group; 7: a 5- to 12-membered monocyclicor polycyclic heterocyclylcarbonyl group; 8: a C₁₋₆ alkoxycarbonylgroup, wherein the alkyl group is optionally substituted with one tothree groups chosen from a halogen atom, a C₁₋₆ alkoxy group, a C₆₋₁₀aryl group, and a 5- to 6-membered monocyclic heterocycle groupoptionally substituted with one to three C₁₋₄ alkyl groups; 9: a C₃₋₁₀cycloalkyloxycarbonyl group, wherein the cycloalkyl group is optionallysubstituted with one to three groups chosen from a halogen atom, anhydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group; 10: a C₆₋₁₀aryloxycarbonyl group, wherein the aryl group is optionally substitutedwith one to three groups chosen from a halogen atom, an hydroxyl group,a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group; 11: a 5- to 12-memberedmonocyclic or polycyclic heterocyclyloxycarbonyl group, wherein theheterocycle group is optionally substituted with one to three groupschosen from a halogen atom, an hydroxyl group, a C₁₋₆ alkyl group, and aC₁₋₆ alkoxy group; 12: a C₁₋₆ alkylsulfinyl group, wherein the alkylgroup is optionally substituted with one to three groups chosen from ahalogen atom, a C₁₋₆ alkoxy group, a C₆₋₁₀ aryl group, and a 5- to6-membered monocyclic heterocycle optionally substituted with one tothree C₁₋₄ alkyl group; 13: a C₃₋₁₀ cycloalkylsulfinyl group, whereinthe cycloalkyl group is optionally substituted with one to three groupschosen from a halogen atom, an hydroxyl group, a C₁₋₆ alkyl group, and aC₁₋₆ alkoxy group; 14: a C₆₋₁₀ arylsulfinyl group, wherein the arylgroup is optionally substituted with one to three groups chosen from ahalogen atom, an hydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxygroup; 15: a 5- to 12-membered monocyclic or polycyclicheterocyclylsulfinyl group, wherein the heterocycle group is optionallysubstituted with one to three groups chosen from a halogen atom, anhydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group; 16: a C₁₋₆alkylsulfonyl group, wherein the alkyl group is optionally substitutedwith one to three groups chosen from a halogen atom, a C₁₋₆ alkoxygroup, a C₆₋₁₀ aryl group, and a 5- to 6-membered monocyclic heterocycleoptionally substituted with one to three C₁₋₄ alkyl groups; 17: a C₃₋₁₀cycloalkylsulfonyl group, wherein the cycloalkyl group is optionallysubstituted with one to three groups chosen from a halogen atom, anhydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group; 18: a C₆₋₁₀arylsulfonyl group, wherein the aryl group is optionally substitutedwith one to three groups chosen from a halogen atom, an hydroxyl group,a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group; 19: a 5- to 12-memberedmonocyclic or polycyclic heterocyclylsulfonyl group, wherein theheterocycle group is optionally substituted with one to three groupschosen from a halogen atom, an hydroxyl group, a C₁₋₆ alkyl group, and aC₁₋₆ alkoxy group; 20: a C₆₋₁₀ aryl group optionally substituted withone to three groups chosen from a halogen atom, an hydroxyl group, aC₁₋₆ alkyl group, and a C₁₋₆ alkoxy group; and 21: a 5- to 12-memberedmonocyclic or polycyclic heterocyclic group, wherein the heterocyclegroup is optionally substituted with one to three groups chosen from ahalogen atom, an hydroxyl group, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxygroup.
 17. The compound of claim 16 or a pharmacologically acceptablesalt thereof, wherein R⁶ is a group chosen from: 1: a hydrogen atom; 2:a C₁₋₆ alkyl group optionally substituted with one to three groupschosen from a halogen atom, a C₁₋₆ alkoxy group, a C₆₋₁₀ aryl group, anda 5- to 6-membered monocyclic heterocyclic group optionally substitutedwith one to three C₁₋₄ alkyl groups; 3: a C₁₋₆ alkylcarbonyl group,wherein the alkyl group is optionally substituted with one to threegroups chosen from a halogen atom, a C₁₋₆ alkoxy group, a C₆₋₁₀ arylgroup, and a 5- to 6-membered monocyclic heterocycle optionallysubstituted with one to three C₁₋₄ alkyl groups; and 4: a C₁₋₆alkylsulfonyl group, wherein the alkyl group is optionally substitutedwith one to three groups chosen from a halogen atom, C₁₋₆ alkoxy group,C₆₋₁₀ aryl group, and a 5- to 6-membered monocyclic heterocycleoptionally substituted with one to three C₁₋₄ alkyl groups.
 18. Thecompound of claim 17 or a pharmacologically acceptable salt thereof,wherein R⁶ is a hydrogen atom.
 19. The compound of claim 1 or apharmacologically acceptable salt thereof, wherein R² is a group chosenfrom: 1: a C₁₋₆ alkyl group optionally substituted with one to threegroups chosen from a halogen atom, an hydroxyl group, an amino groupoptionally substituted with one or two C₁₋₆ alkyl groups, a C₁₋₄ alkoxygroup, a C₃₋₈ cycloalkyl group, and a 5- to 6-membered monocyclicheterocycle group; 2: a C₁₋₆ alkylcarbonyl group; 3: an aminocarbonylgroup, wherein the amino group is optionally substituted with one tothree C₁₋₆ alkyl groups optionally substituted with one to three halogenatoms; and 4: a 3- to 8-membered cyclic aminocarbonyl group, wherein thecyclic amino group is optionally substituted with one to three C₁₋₆alkyl groups.
 20. The compound of claim 1 or a pharmacologicallyacceptable salt thereof, wherein A is O or S; the ring G is either onechosen from the following formula (b) or (e):

R¹ is a hydrogen atom; and R² is a group chosen from: 1: a C₁₋₆ alkylgroup optionally substituted with one to three groups chosen from ahalogen atom, an hydroxyl group, an amino group optionally substitutedwith one or two C₁₋₆ alkyl groups, a C₁₋₄ alkoxy, a C₃₋₈ cycloalkyl, anda 5- to 6-membered monocyclic heterocycle; 2: a C₁₋₆ alkylcarbonylgroup; 3: an aminocarbonyl group, wherein the amino group is optionallysubstituted with one to three C₁₋₆ alkyl groups optionally substitutedwith one to three halogen atoms; and 4: a 3- to 8-membered cyclicaminocarbonyl group, wherein the cyclic amino group is optionallysubstituted with one to three C₁₋₆ alkyl group; and R³, R⁴, and R⁵ arehydrogen atoms.
 21. The compound of claim 1 or a pharmaceuticallyacceptable salt thereof, wherein the compound is chosen from thefollowing compounds: 2-acetylthieno[2,3-g]quinoline-4,9-dione;2-acetylthieno[2,3-g]isoquinoline-4,9-dione;2-(1-hydroxyethyl)thieno[2,3-g]isoquinoline-4,9-dione;2-(2-hydroxypropan-2-yl)thieno[2,3-g]isoquinoline-4,9-dione;2-[cyclopropyl(hydroxy)methyl]thieno[2,3-g]isoquinoline-4,9-dione;N,N-dimethyl-4,9-dioxo-4,9-dihydrothieno[2,3-g]isoquinoline-2-carboxyamide;2-(morpholin-4-ylcarbonyl)thieno[2,3-g]isoquinoline-4,9-dione;N-(2,2-difluoroethyl)-4,9-dioxo-4,9-dihydrothieno[2,3-g]isoquinoline-2-carboxyamide;2-{[ethyl(2-methoxyethyl)amino]methyl}thieno[2,3-g]isoquinoline-4,9-dione;2-{[(2,2-difluoroethyl)amino]methyl}thieno[2,3-g]isoquinoline-4,9-dione;2-[(4-acetylpiperazin-1-yl)methyl]thieno[2,3-g]isoquinoline-4,9-di one;4,9-dioxo-4,9-dihydrothieno[2,3-g]isoquinoline-2-carbonitrile;2-(1-fluoroethyl)thieno[2,3-g]isoquinoline-4,9-dione;2-(3-ethyl-1,2,4-oxadiazol-5-yl)thieno[2,3-g]isoquinoline-4,9-dione;2-acetylthieno[3,2-g]isoquinoline-4,9-dione;N-(2,2-difluoroethyl)-4,9-dioxo-4,9-dihydrofuro[2,3-g]isoquinoline-2-carboxamide;2-(1-hydroxyethyl)furo[3,2-g]isoquinoline-4,9-dione;2-acetylthieno[3,2-f][1]benzofuran-4,8-dione; and2-(morpholin-4-ylcarbonyl)thieno[3,2-f][1]benzofuran-4,8-dione.
 22. Apharmaceutical composition comprising a compound of claim 1 or apharmacologically acceptable salt thereof.
 23. An anticancer agentcomprising a compound of claim 1 or a pharmacologically acceptable saltthereof as an active ingredient.
 24. The anticancer agent according toclaim 23, wherein the cancer is at least one cancer chosen from acuteleukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia,polycythemia vera, malignant lymphoma, brain tumor, head and neckcancer, esophageal cancer, thyroid cancer, small cell lung cancer,non-small-cell lung cancer, breast cancer, gastric cancer, gallbladderbile duct cancer, hepatoma, pancreatic cancer, colon cancer, rectalcancer, chorioepithelioma, endometrial cancer, cervical cancer,urothelial cancer, renal cell cancer, testicular tumor, Wilms' tumor,skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing'ssarcoma, and soft tissue sarcoma.
 25. A method of producing a compoundrepresented by formula (1) or a pharmacologically acceptable saltthereof:

wherein A, R¹, R², R³, R⁴, and R⁵ are defined according to claim 1, andwherein the method is characterized by comprising a step of mixing acompound represented by formula (2) or a salt thereof:

wherein A, R¹, R², R³, R⁴, and R⁵ are defined according to claim 1, orR¹ and R² are optionally substituted alkoxycarbonyl groups; and R⁷ andR⁸ are each C₁₋₆ alkyl optionally substituted with one to three groupschosen from a halogen atom, an hydroxyl group, a C₁₋₄ alkoxy group, aC₆₋₁₀ aryl group, and a 5- to 12-membered monocyclic or polycyclicheterocycle group optionally substituted with one to three C₁₋₆ alkylgroups, with an oxidant.
 26. A compound represented by formula (2) or asalt thereof:

wherein A, R¹, R², R³, R⁴, and R⁵ are defined according to claim 1; andR⁷ and R⁸ are each an C₁₋₆ alkyl group optionally substituted with oneto three groups chosen from a halogen atom, an hydroxyl group, a C₁₋₄alkoxy group, a C₆₋₁₀ aryl group, and a 5- to 12-membered monocyclic orpolycyclic heterocycle group optionally substituted with one to threeC₁₋₆ alkyl groups.